Note: Descriptions are shown in the official language in which they were submitted.
DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.
CECI EST LE TOME 1 DE 2
CONTENANT LES PAGES 1 A 103
NOTE : Pour les tomes additionels, veuillez contacter le Bureau canadien des
brevets
JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME
THIS IS VOLUME 1 OF 2
CONTAINING PAGES 1 TO 103
NOTE: For additional volumes, please contact the Canadian Patent Office
NOM DU FICHIER / FILE NAME:
NOTE POUR LE TOME / VOLUME NOTE:
METHODS AND DEVICES FOR IDENTIFYING BIOMARKERS OF TREATMENT
RESPONSE AND USE THEREOF TO PREDICT TREATMENT EFFICACY
FIELD OF THE INVENTION
The invention features methods and devices for identifying biomarkers of
patient
sensitivity to medical treatments, e.g., sensitivity to chemotherapeutic
agents, and predicting
treatment efficacy using the biomarkers.
BACKGROUND OF THE INVENTION
DNA microarrays have been used to measure gene expression in tumor samples
from
patients and to facilitate diagnosis. Gene expression can reveal the presence
of cancer in a
patient, its type, stage, and origin, and whether genetic mutations are
involved. Gene
expression may even have a role in predicting the efficacy of chemotherapy.
Over recent
decades, the National Cancer Institute (NCI) has tested compounds, including
chemotherapy
agents, for their effect in limiting the growth of 60 human cancer cell lines.
The NCI has also
measured gene expression in those 60 cancer cell lines using DNA microarrays.
Various
studies have explored the relationship between gene expression and compound
effect using
the NCI datasets.
During chemotherapy for cancers critical time is often lost due to a trial and
error
approach to finding an effective therapy. In addition, cancer cells often
develop resistance to a
previously effective therapy. In such situations, patient outcome would be
greatly improved
by early detection of such resistance.
There remains a need for proven methods and devices that predict the
sensitivity or
resistance of cancer patients to a medical treatment.
SUMMARY OF THE INVENTION
The invention features methods and devices for predicting the sensitivity or
resistance
of a patient, e.g., a cancer patient, to a treatment, e.g., treatment with a
compound, such as a
chemotherapeutic agent, or radiation. In particular, the methods and devices
can be used to
1
CA 2631236 2018-01-24
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
predict the sensitivity or resistance of a cancer patient to any medical
treatment, including, e.g.,
treatment with a compound, drug, or radiation. The devices and methods of the
invention have
been used to accurately predict treatment efficacy in cancer patients (e.g.,
patients with lung,
lymphoma, and brain cancer) and can be used to predict treatment efficacy in
patients diagnosed
with any cancer.
Devices employing specific chemosensitivity/ chemoresistance biomarkers for
the
common chemotherapy drugs Vincristine, Cisplatin, Azaguanine, Etopo side,
Adriamycin,
Aclarubicin, Mitoxantrone, Mitomycin, Paclitaxel, Gemcitabine, Taxotere,
Dexamethason.e, Ara-
C, Methylprednisolone, Methotrexate, Bleomycin, Methyl-GAG, Carboplatin, 5-FU
(5-
Fluorouracil), rituximab, radiation, histone deacetylase (HDAC) inhibitors,
and 5-Aza-2'-
deoxycytidine (Decitabine) are also provided. The methods and devices can be
used to predict the
sensitivity or resistance of a subject (e.g., a cancer patient) diagnosed with
a disease condition,
e.g., cancer (e.g., cancers of the breast, prostate, lung and bronchus, colon
and rectum, urinary
bladder, skin, kidney, pancreas, oral cavity and pharynx, ovary, thyroid,
parathyroid, stomach,
brain, esophagus, liver and intrahepatic bile duct, cervix larynx, heart,
testis, small and large
intestine, anus, anal canal and anoreatuna, vulva, gallbladder, pleura, bones
and joints,
hypopharynx, eye and orbit, nose, nasal cavity and middle ear, nasopharyn.x,
ureter, peritoneum,
omentum and mesentery, or gastrointestines, as well as any form of cancer
including, e.g.,
chronic myeloid leukemia, acute lymphocytic leukemia, non-Hodgkin lymphoma,
melanoma,
carcinoma, basal cell carcinoma, malignant mesothelioma, neuroblastoma,
multiple myeloma,
leukemia, retinoblastoma, acute myeloid leukemia, chronic lynaphocytic
leukemia, Hodgkin
lymphoma, carcinoid tumors, acute tumor, or soft tissue sarcoma) to a
treatment, e.g., treatment
with a compound or drug, e.g., a chemotherapeutic agent, or radiation.
In the first aspect, the invention features a method of predicting sensitivity
of a cancer
patient to a treatment for cancer by determining the expression level of at
least one gene in a cell
(e.g., a cancer cell) of the patient, in which the gene is selected from the
group consisting of
ACTB, ACTN4, ADA, ADA1\49, ADAMTS1, ADD1, AF1 Q, AIF1, AKAP 1, AKAP 1 3,
AKRICI, AKT1, ALDH2, ALDOC, ALG5, ALMS1, ALOX15B, AMIG02, AMPD2, AMPD3,
2
=
= =
-= =
= =
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
ANAPC5, ANP32A, ANP32B, ANXA1, AP1G2, AF'OBEC3B, APRT, ARHE, ARHGAP15,
ARHGAP25, ARHGDIB, ARHGEF6, ARL7, ASAH1, ASPH, ATF3, ATIC, ATP2A2,
ATP2A3, ATP5D, ATP5G2, ATP6V1B2, BC008967, BCAT1, BCHE, BCLI1B, BDNF,
BBLBB2, BIN2, BLMH, BMI1, BNIP3, BRDT, BRRNI, BTN3A3, C11 orf2, Cl 4orf139,
C15orf25, Cl 8orf10, Cl orf24, CIorf29, C1orf38, Cl QR1, C22orfl8, C6orf32,
CACNA1G,
CACNB3, CALM1, CALML4, CALU, CAP350, CASP2, CASP6, CASP7, CAST, CBLB,
CCNA2, CCNB 11P I, CCND3, CCR7, CCR9, CD1A, CD1C, CD1D, CD1E, CD2, CD28,
CD3D, CD3E, CD3G, CD3Z, CD44, CD47, CD59, CD6, CD63, CD8A, CD8B1, CD99,
CDC10, CDC14B, CDH11, CDH2, CDKL5, CDICN2A, CDW52, CECR1, CENPB, CENTB1,
CENTG2, CEP1, CG018, CHRNA3, CHS1, CIAPIN1, CICAP4, CICIP-1, CNP, COL4A1,
COL5A2, C0L6A1, CORO1C, CRABP1, CRK, CRY1, CSDA, CTBP1, CTSC, CTSL,
CUGBP2, CUTa, CXCL1, CXCR4, CXorf9, CYFIP2, CYLD, CYR61, DATF'1, DAZAP1,
DBN1, DBT, DCTN1, DDX18, DDX5, DGKA, DIAPH1, DKCI, DKFZP434J154,
DKFZP564C186, DKFZP564G2022, DK_FZp564J157, DKFZP564K0822, DNAJC10, DNAJC7,
DNAPTP6, DOCK10; DOCIC2, DPAGT1, DPEP2, DPYSL3, DSLPI, DUSP1, DXS9879E,
EEF1B2, EFNB2, EHD2, EIF5A, ELIC3, EN02, EPAS1, EPB41L4B, ERCC2, ERG, ERP70,
EVER1, EVI2A, EVL, EXT1, EZH2, F2R, FABP5, FAD104, FAM46A, FAU, FCGR2A,
FCGR2C, FER1L3, FHL1, FHOD1, FKBP1A, FKBP9, FLJ10350, FLJ10539, FLJ10774,
FLJ12270, FLJ13373, FLJ20859, FLI21159, FL322457, FLJ35036, FLJ46603, FLNC,
FLOT1,
FMNL1, FNBP1, FOLH1, FOXF2, FSCN1, FTL, FYB, FYN, GOS2, G6PD, GALIG, GALNT6,
GATA2, GATA3, GFPTI, GIMAP5,. G1T2, GJA1, GLRB, GLTSCR2, GLUL, GMDS, GNAQ,
GNB2, GNB5, GOT2, GPR65, GPRASP1, GPSM3, GRP58, GSTM2, GTF3A, GTSE1, GZMA,
GZMB,H1F0, H1FX, H2AFX, H3F3A, HA-1, HEXB, H1C, HEST1H4C, HK.1, HLA-A, TILA-B,
HLA-DRA, 1-EVIGA1, HMGN2, HMMR, HNRPA1, HNRPD, FINRPM, HOXA9, HRMT1L1,
HSA9761, HSPA5, HS1J79274, HTATSF1, ICAM1, ICAM2, IER3, IF116, IF144, IFITM2,
IFITM3, IFRG28, IGFBP2, IGSF4, IL13RA2, EL21R, IL2RG, 114R, IL6, IL6R, IL6ST,
IL8,
IMPDH2, INPP5D, INSIG1, IQGAP1, IQGAP2, IRS2, ITGA5, ITM2A, JARID2, JUNB, K-
ALPHA-1, ICHDRBS1, K1AA0355, ICIAA0802, KIAA0877, KIAA0922, KTAA1078,
3
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
KIAA1128, KIAA1393, KIFC1, LAIR1, LAMB1, LAMI33, LAT, LBR, LCK, LCP1, LCP2,
LEF1, LEPREI, LGALS1, LGALS9, LHFPL2, LNK, L0054103, L0055831, L0081558,
L0C94105, LONP, LOX, LOXL2, LPHN2, LPXN, LRMP, LRP12, LRR.C5, LRRN3, LST1,
LIB, LUM, LY9, LY96, MAGEB2, MAL, MAP1B, MAP1LC3B, M.AP4K1, MAPK1,
MARCKS, MAZ, MCAM, MCL1, MCM5, MCM7, MDH2, MDNI , MEF2C, MFNG,
MGC17330, MGC21654, MGC2744, MGC4083, MGC8721, MGC8902, MULL, MLPH,
MPHOSPH6, MPP1, MPZL1, MRP63, MRPS2, MT1E, MT1K, MUF1, MVP, MYB, MYL9,
MY01B, NAP1L1 , NAP1E2, NARF, NASP,NCOR2, NDN, NDUFAB1, NDUFS6, NFKB1A,
NID2, NIPA2, NME4, NME7, NNMT, NOL5A, NOL8, NOM02, NOTCH1, NPC1, NQ01,
NR1D2, NUDC, NUP210, N'LTP88, NVL, NXF1, OBFC1, OCRL, OUT, OXA1L, P2RX5,
P4HA1, PACAP, PAF53, PAFAH1B3, PALM2-AKAP2, PAX6, PCBP2, PCCB, PFDN5, PFN1,
PFN2, PGAMI, PHEMX, PHLDA1, PIM2, PITPNC1, PLAC8, PLAGL1, PLAUR, PLCB1,
PLEIC2, PLEKHC1, PLOD2, PLSCR1, PNAS-4, PNMA2, POLR2F, PPAP2B, PRF1, PRG1,
PRIM1, PRKCH, PRKCQ, PRKD2, PRNP, PRP19, PRPF8, PRSS23, PSCDBP, PSIAB9,
PSMC3, PSME2, PTGER4, PTGES2, PTOV1, PTP4A3, PTPN7, PTPNS1, PTRF, PURA,
PWP1, PYGL, QKI, RAB3GAP, RAB7L1, RAB9P40, RAC2, RAF'TL1N, RAG2, RAP1B,
RASGRP2, RBPMS, RCN1, RFC3, RFC5, RGC3, RGS3, RHOH, RIMS3, RIOK3, R1PK2,
RIS1, RNASE6, RNF144, RPL10, RPL I OA, RPL12, RPL13A, RPL17, RPL18, RPL36A,
RPLPO, RPLP2, RPS15, RPS19, RPS2, RPS4X, RPS4Y1, RRAS, RRAS2, RRBP1, RRM2,
RUNX1, RUNX3, S100A4, SART3, SA'T131, SCAP1, SCARB1, SCN3A, SEC31L2, SEC61G,
SELL, SELPLG, SEMA4G, SEPT10, SEPT6, SERPINA1, SERPINB1, SERPINB6, SFRS5,
SFRS6, SFRS7, SH2D1A, SH3GL3, SH3TC1, SHDI, SHMT2, KATI, SKB1, SKP2, SLA,
SLC1A4, SLC20A1, SLC25A15, SLC25A5, SLC39A14, SLC39A6, SLC43A3, SLC4A2,
SLC7A11, SLC7A6, SMAD3, SMOX, SNRPA, SNRPB, SOD2, SOX4, SP140, SPANXC,
SPI1, SRF, SRM, SSA2, SSBP2, SSRP I, SSSCA1, STAG3, STAT1, STAT4, STAT5A,
STC1,
STC2, STOML2, T3JAM, TACC1, TACC3, TAF5, TAL1, TAP1, TARP, TBCA, TCF12, TCF4,
TFDP2, TFPI, TIMM17A, TIMP1, TJP1, 'TK2, TM4SF1, TM4SF2, TM4SF8, TM6SF1,
TMEM2, TMEM22, TMSB10, TMSNB, TINTFAIP3, TNFAIP8, INFRSF10B, TNFRSF1A,
4
=
= " = ==
. - .
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
TNFRSF7, TNIK, TNP01, TOB I, TOMM20, TOX, TPK1, TPM2, TRA@, TRA1, TRAM2,
TRB@, IRD@, TRIM, TRIM14, TRIM22, T1UM28, TR1P13, TRPV2, T1JBGCP3, TUSC3,
TXN, TXNTDC5, UBASH3A, UBE2A, UBE2L6, UBE2S, UCHL1, UCK2, UCP2, UFD1L,
UGDH, ULK2, UM:PS, UNG, USP34, USP4, VASP, VAV1, VLDLR, VWF, WASPIP,
WBSCR20A, WBSCR20C, WNT5A, ZAP70, ZFP36L1, ZNF32, ZNF335, ZNF593,
ZNFN1A1, and ZYX; in which change in the level of expression of the gene
indicates the patient
is sensitive or resistant to the treatment. In an embodiment, the method
includes determining the
expression of two of the listed genes, more preferably three, four, five, six,
seven, eight, nine, or
ten of the listed genes, and most preferably twenty, thirty, forty, fifty,
sixty, seventy, eighty,
ninety, or one hundred or more of the listed genes. In another embodiment, the
change in the
level of gene expression (e.g., an increase or decrease) is determined
relative to the level of gene
expression in a cell or tissue known to be sensitive to the treatment, such
that a similar level of
gene expression exhibited by a cell or tissue of the patient indicates the
patient is sensitive to the
treatment. In another embodiment, the chAnge in the level of gene expression
(e.g., an increase
or decrease) is determined relative to the level of gene expression in a cell
or tissue known to be
resistant to the treatment, such that a similar level of gene expression
exhibited by a cell or tissue
of the patient indicates the patient is resistant to the treatment.
In another embodiment, the at least one gene.is selected from the group
consisting of
RPS4X, S100A4, NDUFS6, Cl4orf139, SLC25A5, RPL10, RPL12, EIF5A, RPL36A, BLMH,
CTBP1, TBCA, MDH2, and DXS9879E, such that an increase in the expression level
of one or
more of these genes indicates that the patient is sensitive to treatment with
Vincristine.
Alternatively, the method.further includes measuring the expression level of
at least one gene
selected from the group consisting of UBB, B2M, MAN1A1, and SUI1, such that an
increase in
the expression level of one or more of these genes indicates that the patient
is sensitive to
treatment with Vincristine.
In another embodiment, the at least one gene is selected from the group
consisting of
ClOR1, SLA, P EPN7, ZNFN1A1, CENTB1, IFII6, AREIGEF6, SEC31L2, CD3Z, GZMB;
CD3D, MAP4K1, GPR65, PRF1, ARHGAP15, TM6SF1, and TCF4, such that an increase
in the.
. .
= = =
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
expression level of one or more of these genes indicates that the patient is
sensitive to treatment
with Cisplatin. Alternatively, the method further includes measuring the
expression level of at
least one gene selected from the group consisting of HCLS1, CD53, PTPRCAP, and
PTPRC,
such that an increase in the expression level of one or more of these genes
indicates that the
patient is sensitive to treatment with Cisplatin.
In another embodiment, the at least one gene is selected from the group
consisting of
SRM, SCARB1, SIAT1, CUGBP2, ICA_Ml, WASP1P, ITM2A, PALM2-AKAP2, PTPNS1,
MF'Pl, LNK., FCGR2A, RUNX3, EVI2A, BTN3A3, LCP2, BCHE, LY96, LCP1,
MCAM,
MEF2C, SLC1A4, FYN, C1orf38, CHS1, FCGR2C, TN1K, AMPD2, SEPT6, RAF'TLIN,
SLC43A3, RAC2, LPXN, CKIP-1, FLJ10539, FLT35036, DOCKI 0, TRPV2, IFRG28, LEF1,
and ADAMTS I, such that an increase in the expression level of one or more of
these genes
indicates that the patient is sensitive to treatment with Azaguanine.
Alternatively, the method
, further includes measuring the expression level of at least one gene
selected from the group
consisting of MSN, SPARC, VW, GAS7, ANPEP, EMP3, BTN3A2, FN.", and CAPN3,
wherein
an increase in expression of said gene indicates that said patient is
sensitive to said treatment and
wherein said treatment is treatment with Azaguanine.
In another embodiment, the at least one gene is selected from the group
consisting of
CD99,1NSIG1, PRGI, MUFI, SLA, SSBP2, GNB5, MFNG, PSIVIB9, EVI2A, PTPN7,
PTG-ER4, CXorf9, ZNF'N1A1, CEN1131, NAP1L1, HLA-DRA, IF116, ARHGEF6, PSCDBP,
SELPLG, LAT, SEC31L2, CD3Z, SH2D1A, GZMB, SCN3A, RAFTLLN, DOCK2, CD3D,
RAC2, ZAP70, GP.R65, PRF1, ARHGAP15, NOTCH1, and UBASH3A, such that an
increase in
the expression level of one or more of these genes indicates that the patient
is sensitive to
treatment with Etopo side. Alternatively, the method further includes
measuring the expression
level of at least one gene selected from the group consisting of LAPTM5, HCLS
I, CD53,
GMFG, PTPRCAP, PTPRC, CORO1A, and ITK, such that an increase in the expression
level of
one or more of these genes indicates that.the patient is sensitive to
treatment with Etoposide.
In another embodiment, the at least one gene is selected from the group
consisting of
CD99, ALDOC, SLA, SSBP2, 1L2RG, CXorf9, RHOH, ZNFN1A1, CENTB1, CD1C, MAP4K1,
6
=
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
CD3G, CCR9, CXCR4, ARHGEF6, SELPLG, LAT, SEC31L2, CD3Z, SH2D IA, CD1A,
LAIR1, TRB@, CD3D, WBSCR20C, ZAP70,1F144, GPR65, AIF1, ARHGAP15, NARF, and
PACAP, such that an increase in the expression level of one or More of these
genes indicates that
the patient is sensitive to treatment with Adriamycin. Alternatively, the
method further includes
measuring the expression level of at least one gene .selected from the group
consisting of
LAPIN'S, HCLS I, CD53, GMFG, PTPRCAP, TCF7, CD1B, PTPRC, COROIA, HEMI, and
ITK, such that an increase in the expression level of one or more of these
genes indicates that the
patient is sensitive to treatment with Adriamycin.
In another embodiment, the at least one gene is selected from the group
consisting of
RPL12, RPLP2, MYB, ZNFN1A1, SCAP1, STAT4, SP140, AMI'D3, TNFAIP8, DDX18,
TAF5, RPS2, DOCK2, GPR65, HOXA9, FLJ12270, and HNRPD, such that an increase in
the
expression level of one or more of these genes indicates that the patient is
sensitive to treatment
with Aclarubicin. Alternatively, the method further includes measuring the
expression level of at
least one gene selected from the group consisting of RPL32, FBL, and PTPRC,
such that an
increase in the expression level of one or more of these genes indicates that
the patient is
sensitive to treatment with Aclarubicin_
In another embodiment, the at least one gene is selected from the group
consisting of
PGA.M1, DPYSL3, INSIUl, GJA1, BNIP3, PRG1, G6PD, PLOD2, LOXL2, SSBP2, Clorf29,
TOX, STC1, TNFRSF1A, NCOR2, NAP1L1, L0C94105, ARHGEF6, GATA3, IFPI, LAT,
CD3Z, AF I Q, MAP1B, IRIM22, CD3D, BCAT1,1F144, CUTC, NAPIL2, NME7, FLJ21159,
and COL5A2, such that an increase in the expression level of one or more of
these genes
indicates that the patient is sensitive to treatment with Mitoxanthrone.
Alternatively, the method
further includes measuring the expression level of at least one gene selected
from the group
consisting of BASP1, COL6A2, PTPRC, PRKCA, CCL2, and RAB31, such that an
increase in
the expression level of one or more of these genes indicates that the patient
is sensitive to
treatment with Mitoxantrone.
In another embodiment, the at least one gene is selected from the group
consisting of =
STC1, GPR65, DOCK10, COL5A2, FA1V146A, and L0054103, such that an increase in
the
7
=
=
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
=
expression level of one or more of these genes indicates that the patient is
sensitive to treatment
with /Vlitomycin.
In another embodiment, the at least one gene is selected from the group
consisting of
RPL10, RPS4X, NUDC, DKC1, DKFZP564C186, PRP19, RAB9P40, HSA9761, GMDS, CEP I,
1L13RA2, MAGEB2, HMGN2, ALMS1, GPR65, FL.110774, NOL8, DAZAP1, SLC25A15,
PAF53, DXS9879E, PITPNC1, SPANXC, and K1AA1393, such that an increase in the
expression level of one or more of these genes indicates that the patient is
sensitive to treatment
with Paclitaxel. Alternatively, the method further includes measuring the
expression level of
RALY, such that an increase in the expression level of one or more of these
genes indicates that
the patient is sensitive to treatment with Paclitaxel.
In another embodiment, the at least one gene is selected from the group
consisting of
PFN1, PGAMI, K-ALPHA-1, CSDA, UCHL1, PWP1, PALM2-AICAP2, TNFRSF1A, ATP5G2,
AF1Q, NME4, and FHOD I, such that an increase in the expression level of one
or more of these
genes indicates that the patient is sensitive to treatment with Gemcitabine.
In another embodiment, the at least one gene is selected from the group
consisting of
ANP32B, GTF3A, RRM2, TRB414, SKP2, TR1P13, RFC3, CASP7, TXN, MCM5, PTGES2,
OBFC1, EPB41L4B, and CALML4, such that an increase in the expression level of
one or more
of these genes indicates that the patient is sensitive to treatment with
Taxotere.
In another embodiment, the at least one gene is selected from the group
consisting of
IFITM2, UBE2L6, USP4, ITM2A, IL2RG, GPRASP1, PTPN7, CXorf9, RHOH, GIT2,
ZNFN1A1, CEP1, TNFRSF7, MAP4K1, CCR7, CD3G, ATP2A3, UCP2, GATA3, CDKN2A,
TARP, LAIR1, SH2D1A, SEPT6, HA-1, ERCC2, CD3D, LST1, ATI., ADA, DATFI,
ARHGAP15, PLAC8, CECR1, LOC81558, and EHD2, such that an increase in the
expression
level of one or more of these genes indicates that the patient is sensitive to
treatment with
Dexamethasone. Alternatively, the method further includes measuring the
expression level of at
least one gene selected from the group consisting of LAPTM5, ITGB2, ANPEP,
CD53, CD37,
ADORA.2A, GNA15, PTPRC, COROIA, I-1FM1, FLEE, and CREB3L1, such that an
increase in
the expression level of one or More of these genes indicates that the patient
is sensitive to
= 8
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
treatment with Dexamethasone.
In another embodiment, the at least one gene is selected from the group
consisting of
ITM2A, RHOH, PRLMI, CENTB1, NAP1L1 ATP5G2, GATA3, PRKCQ, SH2D1A, SEPT6,
NME4, CD3D, CD1E, ADA, and FHOD1, such that an increase in the expression
level of one or
more of these genes indicates that the patient is sensitive to treatment with
Ara-C. Alternatively,
the method further includes measuring the expression level of at least one
gene selected from the
group consisting of GNA15, PTPRC, and RPL13, such that an increase in the
expression level of
one or more of these genes indicates that the patient is sensitive to
treatment with Ara-C.
In another embodiment, the at least one gene is selected from the group
consisting of
CD99, ARHGDIB, VWF, ITM2A, LGALS9, INPP5D, SATB1, l'UDP2, SLA, IL2RG, MFNG,
SELL, CDW52, LRMP, ICAM2, RIMS3, PTPN7, ARHGAP25, LCK, CXorf9, RHOH, GIT2,
ZNFN1A1, CENTB1, LCP2, SPI1, GZMA, CEP1, CD8A, SCAP1, CD2, CD1C, TNFRSF7,
VAV1, MAP4K1, CCR7, C6orf32, AL0X15B, BRDT, CD3G, LTB, ATP2A3, NVL,
RASGRP2, LCP1, CXCR4, PRK.D2, GATA3, TRA@, KIAA0922, TARP, SEC31L2, PRKCQ,
S112D1A, CHRNA3, CD1A, LST1, LAIR.1, CACNAIG, TRB@, SEPT6, HA-1, DOCK2,
CD3D, TRD@, T3JAM, FNBP1, CD6, .AIF1, FOLH1, CD1E, LY9, ADA, CDKL5, TRIM,
EVL, DA __ fF1, RGC32, PRKCH, ARHGAP15, NOTCH I , BIN2, SEMA4G, DPEP2, CECRI,
BCL11B, STAG3, GALNT6, LTBASH3A, PHEMX, F1113373, LEF1, 1L21R, MGC17330,
AKAP13, ZNF335, and GIMAP5, such that an increase in the expression level of
one or more of
these genes indicates that the patient is sensitive.to treatment with
Methylprednisolone.
Alternatively, the method further includes measuring the expression level of
at least one gene
selected from the group consisting of SRRM1, LAPTM5, ITGB2; CD53, CD37, GMFG,
PTPRCAP, GNA15, BLM, PTPRC, CORO1A, PRKCB I , HEM1, and UGT2B17, such that an
increase in the expression level of one or more of these genes indicates that
the patient is
sensitive to treatment with Methylprednisolone.
hi another embodiment, the at least one gene is selected from the group
consisting of
PRPF8, RPL18, GOT2, RPL13A, RPS15, RPLP2, CSDA, KHDRBS1, SNRPA, IMPDH2,
RPS19, NUP88, ATP5D, PCBP2, ZNF593, HSU79274, PRIM1, PFDN5, OXA1L, H3F3A,
9
= = = =
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
ATIC, CIAPIN1, RPS2, PCCB, SHIVIT2, RPLPO, ENRPAI, STOML2, SKB1, GLTSCR2,
CCNBIIP1, MRPS2, FL320859, and FLJ12270, such that an increase in the
expression level of
one or more of these genes indicates that the patient is sensitive to
treatment with Methotrexate.
Alternatively, the method further includes measuring the expression level of
at least one gene
selected from the group consisting of RNPS I, RPL32, EEF1G, PTMA, RPL13, FBL,
RBMX,
and RPS9, such that an increase in the expression level of one or more of
these genes indicates
that the patient is sensitive to treatment with Methotrexate.
In another embodiment, the at least one gene is selected from the group
consisting of
PFNI, HK1, MCL1, ZYX, RAP1B, GN132, EPASI, PGAM1, CKAP4, DUSP1, MYL9, K-
ALPHA-1, LGALS I, CSDA, IFITM2, ITGA5, DPYSL3, JUNI3, NFKBIA, LAMB1, FELL
INSIG1, TIMP1, GJAI PSME2, PRG1, EXT1, DKFZP4341154, MVP, VASP, ARL7, NNMT,
TAP I, PLOD2, ATF3, PALM2-AKAP2, ILS, LOXL2,1L4R, DGKA, STC2, SEC610, RGS3,
F2R, TPM2, PSMB9, LOX, STC1, PTGER4, IL6, SMAD3, WNT5A, BDNF, TNFRSF1A,
FLNC, DKFZP564K0822, FLOT1, PTRF, HLA-B, MGC4083, TNFRSF10B, PLAGL1,
PNIvIA2, TFPI, LAT, GZMB, CYR61, PLAUR, FSCN1, ERP70, AFIQ, HIC, COL6A1,
IFITM3, MAP1B, FLJ46603, RAFTLIN, RRAS, FTL, KLAA0877, MTIE, CDC10, DOCK2,
TRIM22, RIS1, BCATI, PRF1, DBN1, MTIK, TMSB10, FLJ10350, Clorf24, NME7,
TMEM22, TPKI, COL5A2, ELK3, CYLD, ADAIVITS1, EHD2, and ACTB, such that an
increase in the expression level of one or more of these genes indicates that
the patient is
sensitive to treatment with Bleonaycin. Alternatively, the method further
includes measuring the
expression level of at least one gene selected from the group consisting of
MSN, ACTR2,
AKR1131, VIM, ITGA3, OPTN, M6PRBP1, COL 1A1, BASP1, ANPEP, TGFB1, NFII.,3,
NK4,
CSPG2, PLAU, COL6A2, UBC, FGFRI, BAX, COL4A2, and RAB31, such that an increase
in
the expression level of one or more of these genes indicates that the patient
is sensitive to
treatment with Bleomycin.
In another embodiment, the at least one gene is selected from the group
consisting of
SSRP1, NUDC, CTSC, AP102, PSME2, LBR, EFNB2, SERPINAI, SSSCA1, EZH2, MYB,
PRIM1, H2AFX, HMGA1, 1-liMMR, TK2, WHSC1, DIAPH1, LAM-133, DPAGT1, UCK2,
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
SERPINB1, MDN1, BRRN1, GOS2, RAC2, MGC21654, GTSE1, TACC3, PLEK2, PLAC8,
FINRE'D, and PNAS-4, such that an increase in the expression level of one or
more of these
genes indicates that the patient is sensitive to 'treatment with Methyl-GAG.
Alternatively, the
method further includes measuring the expression level of PTMA, such that an
increase in the
expression level of one or more of these genes indicates that the patient is
sensitive to treatment
with Methyl-GAG.
In another embodiment, the at least one gene is selected from the group
consisting of
ITGA5, TNFAIP3, WNT5A, FOXF2, L0C94105, IFI16, LRRN3, DOCK10, LEPRE1, COL5A2,
and ADAMTS1, such that an increase in the expression level of one or more of
these genes
indicates that the patient is sensitive to treatment with Carboplatin.
Alternatively, the method
further includes measuring the expression level of at least one gene selected
from the group
consisting of MSN, VIM, CSPG2, and FGFR1, such that an increase in the
expression level of
one or more of these genes indicates that the patient is sensitive to
treatment with Carboplatin.
In another embodiment, the at least one gene is selected from the group
consisting of
RPL18, RPL10A, ANAPC5, EEF1B2, RPL13A, RPS15, AKAP1, NDUFAB1, APRT, ZNF593, =
MRP63, IL6R, SART3, UCK2, RPL17, RPS2, PCCB, TOMM20, SHMT2, RPLPO, G11,3A,
STOMI2, DKEZp564J157, MRPS2, ALG5, and CALML4, such that an increase in the
expression level of one or more of these genes indicates that the patient is
sensitive to treatment
with 5-Fluorouracil (5-FU). Alternatively, the method further includes
measuring the expression
level of at least one gene selected from the group consisting of RNPS1, RPL13,
RPS6, and
RPL3, such that an increase in the expression level of one or more of these
genes indicates that
the patient is sensitive to treatment with 5-Fluorouracil (5-FU).
In another embodiment, the at least one gene is selected from the group
consisting of
KIFC1, VLDLR, RUNX1, PAFAI-11B3, H1FX, RNF144, TMSNB, CRY1, MAZ, SLA, SRF,
UMPS, CD3Z, PRKCQ, HNRPM, ZAP70, ADD1, RFC5, TM4SF2, PFN2, BMI1, TLTI3GCP3,
ATP6V1B2, CD1D, ADA, CD99, CD2, CNP, ERG, CD3E, CD1A, PSMC3, RPS4Y1, AKT1,
UBE2A, TCF12, UBE2S, CCND3, PAX6, RAG2, GSTM2, SATB1, NASP, IGFBP2,
CDH2, CRABP I, DBN1, AKR.1C1, CACNB3, CASP2, CASP2, LCP2, CASP6, MYB, SFRS6,
11
=
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
GLRB, NDN, GNAQ, TUSC3, GNAQ, JARLD2, OCRL, FBL1, EZH2, SMOX, SLC4A2,
UFD1L, ZNF32, HTATSF1, SBD1, PTOV1, NKR, FYI3, TRLM28, BC008967, TRB@, HI FO,
CD3D, CD3G, CENPB, ALDH2, ANX.A1, H2AFX, CD1E, DDX5, CCNA2, EN02, SNRPB,
GATA3, RRM2, GLUL, SOX4, MAL, LING, ARHGD1B, RUNX1, NIPHOSPH6, DCYN1,
SH3GL3, PLEKHC1, CD47, POLR2F, RHOH, and ADD1, such that an increase in the
expression level of one or more of these genes indicates that the patient is
sensitive to treatment
with Rituxirnab. Alternatively, the method further includes measuring the
expression level of at
least one gene selected from the group consisting of ITK, RALY, PSMC5, MYL6,
CD1B,
STMN1, GNA15, MDK, CAPG, ACTN1, CTNNA1, FARSLA, E2F4, CPSF1, SEPW1, TFRC,
ABL1, TCF7, FGFR1, NUCB2, SMA3, FAT, VIM, and ATP2A3, such that an increase in
the
expression level of one or more of these genes indicates that the patient is
sensitive to treatment
with Rituximab.
In another embodiment, the at least one gene is selected from the group
consisting of.
TRAI, ACTN4, CALM1, CD63, FKBP1A, CALU, IQGAP1, MGC8721, STAT1, TACC1,
TM4SF8, CD59, CKAP4, DUSP1, RCN1, MGC8902, LGALS1, BBLHB2, RRBP1, PRNP,
IER3, MARCKS, LUM, FER1L3, SLC20A1, HEXB, EXT1, TJP1, CTSL, SLC39A6, R101(3,
CRK, NNMT, TRA.M2, ADAM9, DNAJC7, PLSCR1, PRSS23, PLOD2, NPC1, TOBI, GFPTI,
1L8, PYGL, LOXL2, KIAA0355, UGDH, PURA, ULK2, CENTG2, NID2, CAP350, CXCL1,
BTN3A3, IL6, WNT5A, FOXF2, LPHN2, CDH11, P4HAl, GRP58, DS1PI, MAP I LC3B,
GALIG, IGSF4, 1RS2, ATP2A2, OGT, TNFRSF10B, KIAA1128, TM4SF1, RBPMS, RIPK2,
CBLB, NR1D2, SLC7A1 I, MPZL I , SSA2, NQ01, ASPH, ASAH1, MGLL, SERPINB6,
HSPA5, ZFP36L1, C0L4A1, CD44, SLC39A14, NIPA2, FKJ3P9, IL6ST, DKFZP564G2022,
PPAP2B, MAP1B, MAPK1, MY01B, CAST, RRAS2, QKI, LHFPL2, 38970, ARHE,
KIAA1078, FTL, KIAA0877, PLCB1, KIAA0802, RAB3GAP, SERPINB I, TIMM17A, SOD2,
HLA-A, NOM02, L0055 831, PHLDA1, TMEM2, MLPH, FAD104, LRRC5, RAB7L1,
FLJ35036, DOCK10, LRP12, TXNDC5, CDC14B, HRMT1L1, CORO1C, DNAJC10, TNP01,
LONP, AMIG02, DNAPTP6, and ADA1V1TS1, such that an increase in the expression
level of
one or more of these genes indicates that the patient is sensitive to
treatment with radiation
12
. . =
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
therapy. Alternatively, the method further includes measuring the expression
level of at least one
gene selected from the group consisting of WARS, CD81, CTSB, PK12, PPP2CB,
CNN3,
ANXA2, JAK.1, EIF'4G3, COL1A1, DYRK2, NFIL3,ACTN1, CAPN2, BTN3A2, IGFBP3,
FN1, COL4A2, and KPNB1, such that an increase in the expression level of one
or more of these
genes indicates that the patient is sensitive to treatment with radiation
therapy.
In another embodiment, the at least one gene is selected from the group
consisting of
FAU, NOL5A, ANP32A, ARHGDIB, LBR, FABP5, ITM2A, SFRS5, IQGAP2, SLC7A6, SLA,
IL2RG, MFNG, GPSM3, PEW, EVER1, LRMP, ICA.M2, RTIvIS3, FMNL1, MYB, PTPN7,
LCK, CXorf9, RHOH, ZNFN1A1, CENTB1, LCP2, DBT, CEP I, IL6R, VAV1, MAP4KI,
CD28, PTP4A3, CD3G, LTB, USP34, NVL, CD8B1, SFRS6, LCP1, CXCR4, PSCDBP,
SELPLG, CD3Z, PRKCQ, CD IA, GATA2, P2RX5, LAIR.1, Clorf3 8, SH2D1A, TRB@,
SEPT6, HA-1, DOCK2, WBSCR20C, CD3D, RNASE6, SFRS7, WBSCR20A, NUP210, CD6,
BNRPA1, AtFl, CYFIP2, GLTSCR2, Cllorf2, ARHGAP15, BIN2, SH3TC1, STAG3,
TM6SF1, Cl5orf25, FLJ22457, PACAP, and MGC2744, such that an increase in the
expression
level of one or more of these genes indicates that the patient is sensitive to
treatment with histone
deacetylase (HDAC) inhibitor.
In another embodiment, the at least one gene is selected from the group
consisting of
CD99, SNRPA, CUGBP2, STAT5A, SLA, IL2RG, GTSE1, MYB, PTPN7, CXorf9, RHOH,
ZNFN1A1, CENTB1, LCP2, H1ST1H4C, CCR7, APOBEC3B, MCM7, LCP1, SELPLG, CD3Z,
PRKCQ, GZMB, SCN3A, LAIR1, SH2D1A, SEPT6, CG018, CD3D, Cl8orf10, PRF1, AIF'1,
MCM5, LPXN, C22orf18, ARHGAP15, and LEF1, such that an increase in the
expression level
of one or more of these genes indicates that the patient is sensitive to
treatment with 5-Aza-2'-
deoxycytidine (Decitabine).
A second aspect of the invention features a method for determining the
development of
resistance by a patient (i.e,. a cell, such as a cancer cell, in the patient)
to a treatment that the
patient was previously sensitive to. The method includes determining the level
of expression of
one or more of the genes set forth in the first aspect of the invention, such
that an increase in the
expression level of a gene(s) which is decreased in a cell or tissue known to
be sensitive to the
= 13
.=
=
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
treatment indicates that the patient is resistant to or has a propensity to
become resistant to the
treatment. Alternatively, an decrease in the expression level of a gene(s)
which is increased in a
cell or tissue known to be sensitive to the treatment indicates that the
patient is resistant to or has
a propensity to become resistant to the treatment.
A third aspect of the invention features a kit that includes a single-stranded
nucleic acid
(e.g., deoxyribonucleic acid or ribonucleic acid) that is complementary to or
identical to at least 5
consecutive nucleotides (more preferably at least 10, 15, 20, 25, 30, 35, 40,
45, 50, 55, 60, 65, 70,
75, 80, 85, 90, 95, 100, 150, 200, 250, 300, or more consecutive nucleotides;
the nucleic acid can
also be 5-20, 25, 5-50, 50-100, or over 100 consecutive nucleotides long) of
at least one of the
genes set forth in the first aspect of the invention, such that the single
stranded nucleic acid is
sufficient for the detection of expression of the gene(s) by allowing specific
hybridization
between the single stranded nucleic acid and a nucleic acid encoded by the
gene, or a =
complement thereof. The kit further includes instructions for applying nucleic
acids collected
from a sample from a cancer patient (e.g., from a cell of the patient),
determining the level of
expression of the gene(s) hybridized to the single stranded nucleic acid, and
predicting the
patient's sensitivity to a treatment for cancer when use of the kit
establishes that the expression
level of the gene(s) is changes (i.e., increased or decreased relative to a
control sample (i.e.,
tissue or cell) known to be sensitive or resitant to the treatment, as is
discussed above in
connection with the first aspect of the invention). In an embodiment, the
instructions further
indicate that an alteration in the expression level of the gene(s) relative to
the expression of the
gene(s) in a control sample (e.g., a cell or tissue known to be sensitive or
resistant to the
treatment) indioates a change in sensitivity of the patient to the treatment
(i.e., a decrease in the
level of expression of a gene known to be expressed in cells sensitive to the
treatment indicates
that the patient is becoming resistant to the treatment or is likely to become
resistant to the
treatment, and vice versa).
In an embodiment, the kit can be utilized to determine a patient's resistance
or sensitivity
to Vincristine, Cisplatin, Adriarnycin, Etoposide, Azaguanine, Aclarubicin,
Mitoxantrone,
Paclitaxel, Mitomycin, Gemcitabine, Taxotere, Dexamethasone,
Methylprednisolone, Ara-C,
14
=
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
=
Methotrexate, Bleomycin, Methyl-GAG, Rituximab, histone deacetylase (HDAC)
inhibitors, and
5-Aza-2'-deoxycytidine (Decitabine) by determining the expression level of one
or more of the
genes set forth in the first aspect of the invention and known to be increased
in a patient sensitive
to treatment with these agents (i.e., a patient is determined to be sensitive,
or likely to be
sensitive, to the indicated treatment if the level of expression of one or
more of the gene(s)
increases relative to the level of expression of the gene(s) in a control
sample (i.e., a cell or
tissue) in which increased expression of the gene(s) indicates sensitivity to
the treatment, and
vice versa).
In an embodiment, the nucleic acids are characterized by their ability to
specifically
identify nucleic acids complementary to the genes in a sample collected from a
cancer patient.
A fourth aspect of the invention features a method of identifying biomarkers
indicative of
sensitivity of a cancer patient to a treatment for cancer by obtaining
pluralities of measurements
of the expression level of a gene (e.g., by detection of the expression of a
gene using a single
gene probe or by using multiple gene probes directed to a single gene) in
different cell types and
measurements of the growth of those cell types in the presence of a treatment
for cancer relative
to the growth of the cell types in the absence of the treatment for cancer;
correlating each
plurality of measurements of the expression level of the gene in cells with
the growth of the cells
to obtain a correlation coefficient; selecting the median correlation
coefficient calculated for the
gene; and identifying the gene as a biomarker for use in determining the
sensitivity of a cancer
patient to said treatment for cancer if said median correlation coefficient
exceeds 0.3 (preferably
the gene is identified as a biomarker for a patient's sensitivity to a
treatment if the correlation
coefficient exceeds 0.4, 0.5, 0.6, 0.7, 0.8. 0.9, 0.95, or 0.99 or more). In
an embodiment, the
method is performed in the presence of a second treatment.
A fifth aspect of the invention features a method of predicting sensitivity of
a patient
(e.g., a cancer patient) to a treatment for cancer by obtaining a measurement
of a biomarker gene
expression from a sample (e.g., a cell or tissue) from the patient; applying a
model predictive of
sensitivity to a treatment for cancer to the measurement, in which the model
is developed using
an algorithm selected from the group consisting of linear sums, nearest
neighbor, nearest
=
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
=
centroid, linear discriminant analysis, support vector machines, and neural
networks; and
predicting whether or not the patient will be responsive to the treatment for
cancer. In an
embodiment, the measurement is obtained by assaying gene expression of the
biomarker in a cell
known to be sensitive or resistant to the treatment. In another embodiment,
the model combines
the outcomes of linear sums, linear discriminant analysis, support vector
machines, neural
networks, k-nearest neighbors, and nearest centroids, or the model is cross-
validated using a
random sample of multiple measurements. In another embodiment, treatment,
e.g., a compound,
has previously failed to show efficacy in a patient. In several embodiments,
the linear sum is
compared to a sum of a reference population with known sensitivity; the sum of
a reference
population is the median of the sums derived from the population members'
biomarker gene
expression. In another embodiment, the model is derived from the components of
a data set
obtained by independent component analysis or is derived from the components
of a data set
obtained by principal component analysis.
A sixth aspect of the invention features a kit, apparatus, and software used
to implement
the method of the fifth aspect of the invention.
In several embodiments of all aspects of the invention, the expression level
of the gene(s)
is determined by detecting the level of mRNA transcribed from the gene(s), by
detecting the level
of a protein product of the gene(s), or by detecting the level of the
biological activity of a protein
product of the gene(s). In further embodiments of all aspects of the
invention, an increase or
decrease in the expression level of the gene(s), relative to the expression
level of the gene(s) in a
cell or tissue sensitive to the treatment, indicates increased sensitivity of
the cancer patient to the
.treatment. Alternatively, an increase or decrease in the expression level of
the gene(s), relative to
the expression level of the gene(s) in a cell or tissue resistant to the
treatment, indicates increased
resistance of the cancer patient to the treatment. In another embodiment of
all aspects of the
invention, the cell is a cancer cell. In another embodiment of all aspects of
the invention, the
expression level of the gene(s) is measured using a quantitative reverse
transcription-polymerase
chain reaction (qRT-PCR). In an embodiment of all aspects of the invention,
the level of
expression of two of the listed genes is performed, more preferably the level
of expression of
=
16
::=== : .. = =
. = =
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
three, four, five, six, seven, eight, nine, or ten. of the listed genes is
perfoinied, and most
preferably twenty, thirty, forty, fifty, sixty, seventy, eighty, ninety, or
one hundred or more of the
= listed genes is performed. In another embodiment of all aspects of the
invention, the expression
level of the gene(s) is determined using the kit of the third aspect of the
invention.
In another embodiment of all aspects of the invention, the treatment is a
compound, such
as a chemotherapteutic agent selected from the group consisting of
Vincristine, Cisplatin,
Adriarnycin, Etoposide, Azaguanine, Aclarubicin, Mitoxantrone, Paclitaxel,
Mitomycin,
Gemcitabine, Taxotere, Dexamethasone, Methylprednisolone, Ara-C, Methotrexate,
Bleomycin,
Methyl-GAG, Rituximab, histone deacetylase (F1DAC) inhibitors, and 5-Aza-2'-
deoxycytidine
(Decitabine). In another embodiment of all aspects of the invention, the
compound has
previously failed to show effect in a subject (e.g., a subject selected from a
subpopulation
predicted to be sensitive to the treatment, a subject selected from a
subpopulation predicted to die
without treatment, a subject selected from a subpopulation predicted to have
disease symptoms
without treatment, a subject selected from a subpopulation predicted to be
cured without
= treatment.
In another embodiment of all aspects of the invention, the treatment is, e.g.,
administration of a compound, a protein, an antibody, an oligonucleotide, a
chemotherapeutic
agent, or radiation to a patient. In an emobodiment of all aspects of the
invention, the treatment
is, e.g., a chemotherapeutic agent, such as, e.g., Vincristine, Cisplatin,
Azaguanine, Etoposide,
Adriamycin, Aclarubicin, Mitoxantrone, Mitomycin, Paclitaxel, Genacitabine,
Taxotere,
Dexamethasone, Ara-C, Methylprednisolone, Methotrexate, Bleomycin, Methyl-GAG,
Carboplatin, 5-FU (5-Fluorouracil), MABTHERAirm (Rituximab), histone
deacetylase (1-IDAC)
inhibitors, 5-Aza-2'-deoxycytidine (Decitabine), alpha emitters such as
astatine-211, bismuth-
212, bismuth-213, lead-212, radium-223, actinium-225, and thorium-227, beta
emitters such as
tritium, strontium-90, cesium-137, carbon-11, nitrogen-13, oxygen-15, fluorine-
18, iron-52,
cobalt-55, cobalt-60, copper-61, copper-62, copper-64, zinc-62, zinc-63,
arsenic-70, arsenic-71,
arsenic-74, bromine-76, bromine-79, rubidium-82, yttrium-86, zirconium-89,
indium-110,
iodine-120, iodine-124, iodine-129, iodine-131, iodine-125, xenon-122,
technetium-94m,
=
17
= : = = . =. - = =.
= = =
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
technetium-94, technetium-99m, and technetium-99, gamma emitters such as
cobalt-60, cesium-
137, and technetium-99m, Alemtuzumab, Daclizumab, Rituximab (MABTHERAT:14),
Trastununab (IIERCEPTIN114), Gemtuzumab, Ibritwnomab, Edrecolomab,
Tositu.momab,
CeaVac, Epratuzumab, Mitumomab, Bevacizumab, Cetuximab, Edrecolomab,
Lintuzumab,
MDX-210, IGN-101, MDX-010, MAb, AME, ABX-EGF, EMD 72000, Apolizumab,
Labetuzumab, ior-tl, MDX-220, MRA, H-11 scFv, Oregovomab, hu.T591 MAb, BZL,
VisilizUmab, TriGem, TriAb, R3, MT-201, G-250, unconjugated, ACA-125, Onyvax-
105, CDP-
860, BrevaRex MAb, AR54, TMC-1C11, GlioMAb-H, ING-1, Anti-LCG MAbs, MT-103,
KSB-
303, Therex, KW-2871, Anti-HMI.24, Anti-PTHrP, 2C4 antibody, SGN-30, TRAIL-RI
MAb,
CAT, Prostate cancer antibody, H22xKi-4, ABX-MA1, Imuteran, Monopharm-C,
Acivicin,
Aclarubicin, Acodazole Hydrochloride, Acronine, Adozelesin, Adriamycin,
Aldesleukin,
Altretamine, Ambomycin, A. metantrone Acetate, Arninoglutethimide, Amsacrine,
Anastrozole,
Anthramycin, Asparaginase, Asperlin, Azacitidine, Azetepa, Azotomycin,
Batimastat,
Benzodepa, Bicalutqmide, Bisantrene Hydrochloride, Bisnafide Dimesylate,
Bizelesin,
Bleomycin Sulfate, Brequinar Sodium, Bropirimine, Busulfan, Cactinomycin,
Calusterone,
Caraptothecin, Caracemide, Carbetimer, Carboplatin, Carmustine, Carubicin
Hydrochloride,
Carzelesin, Cedefingol, Chlorambucil, Cirolemycin, Cisplatin, Cladribine,
Combretestatin A-4,
Crisnatol Mesylate, Cyclophosphamide, Cytarabine, Dacarbazine, DACA (N- [2-
(Dimethyl-
amino) ethyl] acridine-4-carboxarnide), Dactinomycin, Daunorubicin
Hydrochloride,
Daunomycin, Decitabine, Dexormaplatin, Dezag,uanine, Dezaguanine Mesylate,
Diaziquone,
Docetaxel, Dolasatins, Doxorubicin, Doxorubicin Hydrochloride, Droloxifene,
Droloxifene
Citrate, Dromostanolone Propionate, Duazomycin, Edatrexate, Eflomithine
Hydrochloride,
Ellipticine, Elsarnitrucin, Enloplatin, Enpromate, Epipropidine, Epirubicin
Hydrochloride,
Erbulozole, Esorubicin Hydrochloride, Estramustine, Estramustine Phosphate
Sodium,
Etanidazole, Ethiodized Oil 1131, Etoposide, Etoposide Phosphate, Etoprine,
Fadrozole
Hydrochloride, Fazarabine, Fenretinide, Floxuridine, Fludarabine Phosphate,
Fluorouracil, 5-
FdUMP, Flurocitabine, Fosquidone, Fostriecin Sodium, Gemcitabine, Gemcitabine
Hydrochloride, Gold Au 198, Homocamptothecin, Hydroxyurea, Idarubicin
Hydrochloride,
18
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
Ifosfamide, Ilmofosine, Interferon Alfa-2a, Interferon Alfa-2b, Interferon
Alfa-nl, Interferon
Alfa-n3, Interferon Beta-I a, Interferon Gamma-I b, Iproplatin, Irinotecan.
Hydrochloride,
Lanreotide Acetate, Letrozole, Leuprolide Acetate, Liarozole Hydrochloride,
Lornetrexol
Sodium, Lomustine, Losoxantrone Hydrochloride, Masoprocol, Maytansine,
Mechlorethamine
Hydrochloride, Megestrol Acetate, Melengestrol Acetate, Melphalan, Menogaril,
Mercaptopurine, Methotrexate, Methotrexate Sodium, Metoprine, Meturedepa,
Mitindoraide,
Mitocarcin, Mitocromin, Mitogillin, Mitomalcin, Mitomycin, Mitosper, Mitotane,
Mitoxantrone
Hydrochloride, Mycophenolic Acid, Nocodazole, NogaIaraycin,Orrnaplatin,
Oxisuran, Paclitaxel,
Pegaspargase, Peliomycin, Pentamustine, PeploycinSulfate, Perfosfamide,
Pipobroman,
Piposulfan, Piroxantrone Hydrochloride, Plicamycin, Plomestane, Porfuner
Sodium,
Porfiromycin, Prednimustine, Procarbazine Hydrochloride, Puromycin, Puromycin
Hydrochloride, Pyrazofurin, Rhizoxin, Rhizoxin D, Riboprine, Rogletimide,
Safmgol, Safingol
Hydrochloride, Semustine, Simtrazene, Sparfosate Sodium, Sparsomycin,
Spirogermanium
Hydrochloride, Spiromustine, Spiroplatin, Streptonigrin, Streptozocin,
Strontium Chloride Sr 89,
Sulofenur, Talisomycin, Taxane, Taxoid, Tecogalan Sodium, Tegafur,
Teloxantrone
Hydrochloride, Ternoporfm, Teniposide, Terwdrone, Testolactone, Thiamiprine,
Thioguanine,
Thiotepa, Thymitaq, Tia.zofurin, Tirapazamine, Tomudex, T0p53, Topotecan
Hydrochloride,
Toremifene Citrate, Trestolone Acetate, Triciribine Phosphate, Trimetrexate,
Trimetrexate
Glucuronate, Triptorelin, Tubulozole Hydrochloride, Uracil Mustard, Uredepa,
Vapreotide,
Verteporfin, Vinblastine, Vinblastine Sulfate, Vincristine, Vincristine
Sulfate, Vindesine,
Vindesine Sulfate, Vinepidine Sulfate, Vinglycinate Sulfate, Vinleuroshae
Sulfate, Vinorelbine.
Tartrate, Vinrosidine Sulfate, Vinzolidine Sulfate, Vorozole, Zeniplatin,
Zinostatin, Zorubicin
Hydrochloride, 2-Chlorodeoxyadenosine, 2' Deoxyformycin, 9-aminocamptothecin,
raltitrexed,
N-propargy1-5,8-dideazafolic acid, 2chloro-2'-arabino-fluoro-2'-
deoxyadenosine, 2-chloro-2'-
deoxyadenosine, anisornycin, trichostatin A, hPRL-G129R, CEP-751, linomide,
sulfur mustard,
nitrogen mustard (mechlor etharnine), cyclophosphamide, melphalan,
chlorambucil, ifosfamide,
busulfan, N-methyl-Nnitrosourea (MNU), N, N'-Bis (2-chloroothyl)-N-nitrosourea
(BCNIJ), N-
(2-chloroethyl)-N' cyclohexyl-N-nitrosourea (CCNU), N- (2-chloroethyl)-N'-
(trans-4-
19
=
:=*': . "' . .:':'== = :' . = .. .
= == .= =
. .
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
=
methylcyclohexyl-N-nitroso-urea (MeCCNU), N- (2-chloroetlay1)-N'- (diethyl)
ethylphosphonate-
N-nitrosourea (fotemustine), streptozotoein, diacarbazine (DTIC),
mitozolonaide, temozolomide,
thiotepa, mitomycin C,'AZQ, adozelesin, Cisplatin, Carboplatin, Ormaplatin,
Oxaliplatin,C1-
973, DWA 2114R, 3M216, IM335, Bis (platinum), tomudex, azacitidine,
cytarabine,
gemcitabine, 6-Mercaptopurine, 6-Thioguanine, Hypoxanthine, teniposide 9-amino
camptotheein, Topotecan, CPT-11, Doxorubiein, Daunomyein, darubicin,
mitoxantrone, losoxantrone, Dactinomycin. (Actinomycin D), amsacrine,
pyrazoloacridine, all-
trans retinol, 14-hydroxy-retro-retinol, all-trans retinoic acid, N- (4-
Hydroxyphenyl) retinarnide,
13-cis retinoic acid, 3-Methyl TTNEB, 9-cis retinoic acid, fludarabine (2-F-
ara-AMP), 2-
chlorodeoxyadenosine (2-Cda), 20-pi-1,25 dihydroxyvitamin D3, 5-ethynyluracil,
abiraterone,
aclarubicin, acylfulvene, adecypenol, adozelesin, aldesleukin, ALL-TK
antagonists, altretamine,
anibamustine, amidox, amifostine, aminolevulinic acid, arruubicin, amsacrine,
anagrelide,
anastrozole, andrographolide, angiogenesis inhibitors, antagonist D,
antagonist G, antarelix, anti-
dorsalizing morphogenetic protein-1, antiandrogen, prostatic carcinoma,
antiestrogen,
antineoplaston, antisense oligonucleotides, aphidicolin glycinate, apoptosis
gene modulators,
apoptosis regulators, apurinic acid, ara-CDP-DL-PIBA, argininedearainase,
asulacrine,
atamestane, atrimustine, axinastatin 1, axinastatin 2, axinastatin 3,
azasetron, azatoxin,
azatyrosine, baccatin ifi derivatives, balanol, batim.astat, BCRJABL
antagonists, benzochlorins,
benzoylstaurosporine, beta lactam derivatives, beta-alethine, betaclamycin B,
betulinic acid,
bFGF inhibitor, bicalutamide, bisantrene, bisaziridinylspermine, bisnafide,
bistraten.e A,
bizelesin, breflate, bleomycin A2, bleomycin B2, bropirimine, budotitape,
buthionine
sulfoximine, calcipotriol, calphostin C, camptothecin derivatives (e.g., 10-
hydroxy-
camptothecin), canarypox IL-2, capecitabine, carboxamide-amino-triazole,
carboxyamidotriazole, CaRest M3, CARN 700, cartilage derived inhibitor,
carzelesin, casein
kinase inhibitors (ICOS), castanospennine, cecropin B, cetrorelix, chlorins,
chloroquinoxaline
sulfonamide, cicaprost, cis-porphyrin, cladribine, clomifene analogues,
clotrimazole, collismycin
A, collismycin B, combretastatin A4, combretastatin analogue, conagenin,
crambescidin 816,
crisnatol, cryptophycin 8, cryptophycin A derivatives, curacin A,
cyclopentanthraquinones,
=
= = .. .
- =
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
cycloplatarn, cypenaycin, cytarabine ocfosfate, cytolytic factor, cytostatin,
daclbrimab, decitabine,
dehydrodidemnin B, 2'deoxycoformycin (DCF), deslorelin, dexifosfamide,
dexrazoxane,
dexverapamil, diaziquone, didemnin B, didox, diethylnorspermine, dihydro-5-
azacytidine,
dihydrotaxol, 9- , dioxarnycin, diphenyl spiromustine, discodermolide,
docosanol, dolasetron,
doxifluridine, droloxifene, dronabinol, duocarmycin SA, ebselen, ecomustine,
edelfosine,
edrecoIornab, eflornithine, elemene, emitefur, epirubicin, epothilones (A, R =
H, B, R = Me),
epithilones, epristeride, estramustine analogue, estrogen agonists, estrogen
antagonists,
etanidazole, etoposide, etoposide 4'-phosphate (etopofos), exemestane,
fadrozole, fazarabine,
fenretinide, filgrastim, finasteride, fiavopiridol, flezelastine, flunsterone,
fludarabine,
fluorodaunorunicin hydrochloride, forfenimex, founestane, fostriecin,
fotemustine, gadolinium
texaphyrin, gallium nitrate, galocitabine, ganirelix, gelatinase inhibitors,
gemcitabine, glutathione
inhibitors, hepsulfam, heregulin, hexamethylene bisacetamide,
homoharringtonine (HHT),
hypericin, ibandronic acid, idarubicin, idoxifene, idramantone, ilmofosine,
ilomastat,
imirlayoacridones, imiquimod, irnmunostimulant peptides, insulin-like growth
factor-1 receptor
inhibitor, interferon agonists, interferons, interleukins, iobenguane,
iododoxorubicin, ipomeanol,
4-, irinotecan, iroplact, irsogladine, isobengazole, isohomohalicondrin B,
itasetron,
jasplakinolide, kahalalide F, lamellarin-N triacetate, lanreotide, leinamycin,
lenograstim, lentinan
sulfate, leptolstatin, letrozole, leukemia inhibiting factor, leukocyte alpha
interferon, leuprolide +
estrogen + progesterone, leuprorelin, levamisole, liarpzole, linear polyamine
analogue, lipophilic
disaccharide peptide, lipophilic platinum compounds, lissoclinamide 7,
lobaplatin, lombricine,
loraetrexol, lonidamine, losoxantrone, lovastatin, loxoribine, lurtotecan,
lutetium texaphyrin,
lysofylline, lytic peptides, maytansine, mannostatin A, marimastat,
masoprocol, maspin,
matrilysin inhibitors, matrix metalloproteinase inhibitors, menogatil,
rnerbarone, meterelin,
methioninase, metoclopramide, MIF inhibitor, ifepristotte, miltefosine,
mirimostim, mismatched
double stranded RNA, mithracin, mitogoa7one, mnitolactol, mitomycin analogues,
mitonafide,
mitotoxin fibroblast growth factor-saporin, mitoxaptrone, mofarotene,
molgramostim,
monoclonal antibody, human chorionic gonadotrophin, monophosphoryl lipid A +
myobacterium
cell wall sk, .mopidanaol, multiple drug resistance gene inhibitor, multiple
tumor suppressor 1-
21
=
. = =
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
based therapy, mustard anticancer agent, mycaperoxide B, mycobacterial cell
walextract,
myriaporone, N-acetyldinaline, N-substituted benzamides, nafarelin, nagrestip,
naloxone +
pentazocine, napavin, naphterpirt, nartograstim, nedaplatin, nemorubicin,
neridronic acid, neutral
endopeptidase, iiilntamide, nisamycin, nitric oxide modulators, nitrwdde
antioxidant, nitrullyn,
06-benzylgunnine, octreotide, okicenone, oligonucleotides, onapristone,
ondansetron,
ondansetron, oracin, oral cytokine inducer, ormaplatin, osaterone,
oxaliplatin, oxaunomycin,
paclitaxel analogues, paclitaxel derivatives, palauamine, palmitoylrhizoxin,
parnidronic acid,
panaxytriol, panomifene, parabactin., pazelliptine, pegaspargase, peldesine,
pentosan polysulfate
sodium, pentostatin, pentrozole, perflubron, perfosfamide, perillyl alcohol,
phenazinomycin,
phenylacetate, phosphatase inhibitors, picibanil, pilocarpine hydrochloride,
pirarubicin,
piritrexim, placetin A, placetin 13, plasminogen activator inhibitor, platinum
complex, platinum
compounds, platinuna-triamine complex, podophyllotoxin, porfimer sodium,
porfiromycin,
propyl bis-acridone, prostaglandin J2, proteasome inhibitors, protein A-based
immune
modulator, protein kinase C inhibitor, protein kinase C inhibitors,
rnicroalgal, protein tyrosine
phosphatase inhibitors, purine nucleoside phosphorylase inhibitors, purpurins,
pyrazoloacridine,
pyridoxylated hemoglobin polyoxyethylene conjugate, raf antagonists,
raltitrexed, rarnosetron,
ras farnesyl protein transferase inhibitors, ras inhibitors, ras-GAP
inhibitor, retelliptine
demethylated, rhenium Re 186 etidronate, rhi70dn, ribozrales, Ril retinamide,
rogletimide,
rohitukine, romurtide, roquinimex, rubiginone B 1, ruboxyl, safmgoI,
saintopin, SarCNU,
sarcophytol A, sargrarnostim, Sdi 1 mimetics, semtustine, senescence derived
inhibitor 1, sense
oligonucleotides, signal transduction inhibitors, signal transduction
modulators, single chain
antigen binding protein, sizofiran, sob-uzoxane, sodium borocaptate, sodium
phenylacetate,
solverol, somatomedin binding protein, sonermin, sparfosic acid, spicamycin D,
.spiromustine,
splenopentin, spongistatin 1, sqnalamine, stem cell inhibitor, stem-cell
division inhibitors,
stipiamide, stromelysin inhibitors, sulfinosine, superactive vasoactive
intestinal peptide
antagonist, suradista, suramin, swainsonine, synthetic glycosaminoglycans,
tallimustine,
tamoxifen methiodide, tauromustine, tazarotene, tecoga1an sodium, tegafur,
tellurapyrylium,
telomerase inhibitors, temoporfin, temozolomide, teniposide,
tetrachlorodecaoxide, tetrazomine,
= 22
=
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
thaliblastine, thalidomide, thiocoraline, thrombopoietin, thrombopoietin
mimetic, thyrnalfasin,
thymopoietin receptor agonist, thymotrinan, thyroid stimulating hormone, tin
ethyl etiopurpurin,
tirapazamine, titanocene dichloride, topotecan, topsentin, toremifene,
totipotent stem cell factor,
translation inhibitors, tretinoin, triacetyluridine, hticiribine,
trimetrexate, triptorelin, tropisetron,
turosteride, tyrosine kinase inhibitors, tyrphostins, UJ3C inhibitors,
ubenimex, urogenital sinus-
derived growth inhibitory factor, urolcinase receptor antagonists, vapreotide,
variolin B, vector
system, erythrocyte gene therapy, velaresol, veramine, verdins, verteporfm,
vinorelbine,
vinxaltine, vitaxin, vorozole, zanoterone, zeniplatin, zilascorb, or
zinostatin. stimalamer. In
another embodiment of all aspects of the invention, a second treatment is
utilized to determine
gene expression in a sample from the patient_
In another embodiment of all aspects of the invention, the gene is selected
from the group
consisting of ABL1, AC1.13, ACTN1, ACTN4, ACTR2, ADA, ADAM9, ADAMTS1, ADD1,
ADORA2A, AF1Q, AIFI, AKAP1, AKAP13, AKR1B1, AKR.1C1, AKT1, ALDH2, ALDH3A1,
ALDOC, ALG5, ALMS1, AL0X15B, AMIG02, AMPD2, AMPD3, ANAPC5, ANP32A,
ANP32B, ANPEP, ANXA1, ANXA2, AP1G2, APOBEC3B, APRT, ARTIE, ARHGAP15,
ARHGAP25, ARHGDEB, ARHGEF6, ARL7, ASAH1, ASPH, A11.3, ATIC, ATOX1, ATP1B3,
ATP2A2, ATP2A3, ATP5D, ATP5G2, ATP6V1B2, B2M, BASP1, BAX, BC008967, BCAT1,
BCHE, BCL11B, BDNF, BBIBB2, BIN2, BLM, BLMH, BLVRA,BM[1, BNIP3, BRDT,
BRRN1, BTN3A2, BTN3A3, CI I orf2, C 1 4orf139, Cl5orf25, Cl8orfl 0, C1orf24, C
1 orf29,
Clorf38, C1QR1, C22orf18, C5orf13, C6orf32, CACNA1G, CACNB3, CALD1, CALM1,
CALML4, CALU, CAP350, CAPG, CAPN2, CAPN3, CASP2, CASP6, CASP7, CAST, CBFB,
CBLB, CBRI, CBX3, CCL2, CCL21, CCNA2, CCNB1T1, CCND3, CCR7, CCR9, CCT5,
CD151, CD1A, CD1B, CD1C, CD1D, CDIE, CD2, CD28, CD37, CD3D, CD3E, CD3G, CD3Z,
CD44, CD47, CD53, CD59, CD6, CD63, CD81, CD8A, CD8B1, CD99, CDC10, CDC14B,
CDH11, CDH2, CDKL5, CDKN2A, CDW52, CECR1, CENPB, CENTB1, CENTG2, CEP1,
CG018, CHRNA3, CHS1, CIAPINl, CKAP4, CKIP-I, CNN3, CNP, COL1A1, C0L4A1,
COL4A2, 00L5A2, COL6A1, COL6A2, COPA, COPEB, CORO1A, CORO1C, COX7B,
CPSFI, CRABP1, CREB3LI, CRIP2, CRK, CRYI, CSDA, CSPG2, CSRP1, CST3, CTBP1,
23
. .
. = = =
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
CTGF, CTNNA1, CTSB, CTSC, CTSD, CTSL, CUGBP2, CUTC, CXCLI, CXCR4, CXorf9,
CYFIP2, CYLD, CYR6I, DATF I, DAZAP1, DBN1, DBT, DCTN I, DDOST, DDX18, DDX5,
DGKA; DIAPH1, DIPA, DKC1, DICFZP434J154, DKFZP564C186, DKFZP564G2022, =
DKFZp564J157, DKFZP564K0822, DNAJC10, DNAPTP6, DOCK10, DOCK2, DPAGT1, =
DPEP2, DPYSL3, DSIPI, DUSP 1 , DUSP3, DXS9879E, DYRK2, E2F4, ECE1, ECM1,
EEF1A1, EEF1B2, EEFIG, EFNI32, EHD2, EIF2S2, ElF3S2, ElF4B, EIF4G3, EIF5A,
ELA2B,
ELK3, EMP3, EN02, EPAS1, EPB41L4B, ERCC2, ERG, ERP70, EVERI, EV12A, EVL,
EXT1, EZH2, F2R, FABP5, FAD104, FAM46A, FARSLA, FAT, FAU, FBL, FCGR2A,
FCGR2C, FER1L3, FGFRI, FHL1, FHOD1, FICBP1A, FKBP9, FLU, FL310350, FL110539,
FLJ10774, FLJ12270, FLT13373, FLJ20859, FLJ21159, FLJ22457, FL335036,
FLJ46603,
FLNC, FLOTI, F1vLNL1, FN1, FNBP1, FOLHI, FOXF2, FSCN1, FSTL1, FTH1, FTL, FYB,
FYN, GOS2, G6PD, GALIG, GALNT6, GA.PD, GAS7, GATA2, GATA3, GFPTI, GIMAP5,
GIT2, GJA1, GLRB, GLTSCR2, GLUL, GMDS, GMFG, GNA15, GNAI2, GNAQ, GNB2,
GNB5, GOT2, GPINTM03, GPR65, GPRASP1, GPSM3, GRP58, GSTM2, GTF3A, GTSE1,
GYPC, GZMA, GZMB, HIT , H1FX, H2AFX, H3F3A, HA-1, HCLS1, FIEM1, HEXB, HIC,
HIST1H4C, HK1, HLA-A, 111A-B, ELA-DRA, HMGA1, EMGB2, LIMGN2, HMMR,
HNRPA1, HNRPD, FINRPM, HOXA9, HPRT1, FIRMT1L1, HSA9761, HSPA5, HSU79274,
HTATSFI, H156800, ICAM1, ICAM2, IER3, 1F116, 1F144, EF1TM2, 1FITM3, IIRG28,
IGFBP2,
IGFBP3, IGSF4, IL13RA2, IL21R, IL2RG, IL4R, IL6, IL6R, IL6ST, IL8, IMPDH2.,
INPP5D, =
INSIGI , IQGAP I, IQGAP2, IR.S2, ITGA3, ITGA5, ITGB2, ITK, ITM2A, JAKI,
JARID2,
JUNB, K-ALPHA-I, ICHDRBS1, KIAA0220, KIAA0355, KLAA0802, KIAA.0877, KIAA0922,
K1AA1078, KLAA1128, KIAA1393, KIFC1, KPNB1, LAIR.1, LAMB1, LAMB3, LAMR1,
LAPTM5, LAT, LBR, LCK, LCPI, LCP2, LDHB, LEF1, LEPRE1, LGALS1, LGALS9,
LIIFPL2, LMNB1, LNK, L0054103, L0055831, L0081558, L0C94105, LONP, LOX,'
LOXL2, LPHN2, LPXN, LRMP, LRP12, LRRC5, LRRN3, LST1, LTB, LUM, LY9, LY96,
M6PRBP1, MAD2L1BP, MAGEB2, MAL, MAN1A1 , MAP1B, MAPILC3B, MAP4K1,
MAPK1, MAPRE1, MARCKS, MAZ, MCAM, MCL1, MCM5, MCM7, MDH2, MDK, MDN1,
MEF2C, MENG, MG017330, MGC21654, MGC2744, MGC4083, MGC8721, MGC8902,
24
. .
= " = = .
= =
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
MGLL, MIA, MICA, MLPH, MME, MMP2, MPHOSPH6, 1v1PP1, MPZL1, MRP63, MRPL12,
MRPS2, MSN, MT1E, MT1K, MUF1, MVP, MYB, MYC, MYL6, MYL9, MY01B, NAP1L1,
NAP1L2, NARF, NARS, NASP, NBL1, NCL, NCOR2, NDN, NDUFAB1, NDUFS6, NFIL3,
NFKBIA, NID2, NIPA2, NK4, NME4, NME7, NNMT, NOL5A, NOL8, NOM02,NOTCH1,
NPC1, NQ01, NR.1D2, NUCB2, NUDC, NUP210,NUP88, NVL, NXF1, OBFC1, OCRL, OGT,
OK/SW-c1.56, OPTN, OXA1L, P2RX5, P4HA1, PACAP, PAF53, PAFAH1B3, PALM2-
AKAP2, PAX6, PBEF1, PCBP2, PCCB, PEA15, PFDN5, PFN1, PFN2, PGAM1, PGIC1,
PHElVf, PHLDA1, PIM2, PITPNC1, PICM2, PLAC8, PLAGL1, PLAU, PLAUR, PLCB1,
PLEK2, PLEKHC1, PLOD2, PLSCR1, PNAS-4, PNMA2, POLR2F, PON2, PPAP2B, PPIA,
PP1F, PPP1R11, PFP2CB, PRF1, PRG1, PRIM1, PRKCA, PRKCB1, PRKCH, PRKCQ,
PRKD2, PRNP, PRP19, PRPF8, PRPS1, PRSS11, PRSS23, PSCDBP, PSMB9, PSMC3,
PSMC5, PSME2, PTGER4, PTGES2, PTMA, PTOV1, PTP4A3, PTPN7, PTPNS1, PTPRC,
PTPRCAP, PTRF, PTS, PURA, PWP1, PYGL,.QKI, RAB31, RAB3GAP, RAB7, RAB7L1,
RAB9P40, RAC2, RAFTL1N, RAG2, RALY, RAP1B, RASGRP2, RBMX, RBPMS, RCN1,
REA, RFC3, RFC5, RGC32, RG-S3, RHOC, RHOH, RIMS3, RIOK3, RIPIC2, RIS1, RNASE6,
RINF144, RNPS1, RPL10, RPL1OA, RPL11, RPL12, RPL13, RPL13A, RPL17, RPL18,
- RPL18A, RPL24, RPL3, RPL32, RPL36A, RPL39, RPL7, RPL9, RPLPO, RPLP2, RPS10,
RPS11, RPS15, RPS15A, RPS19, RPS2, RI'S23, RPS24, RPS25, RPS27, RPS28, RPS4X,
RPS4Y1, RPS6, RPS7, RPS9, RRAS, RRAS2, RRI3P1, RR1v12, RUNX1, RUNX3, S100A13,
S100A4, SART3, SATB1, SCAP1, SCARB1, SCARB2, SCN3A, SCTR, SEC31L2, SEC61G,
SELL, SELPLG, SEMA4G, SEPT6, SEPT10, SEPW1, SERPINA1, SERPINB1, SERPINB6,
SFRS3, SFRS5, SFRS6, SFRS7, SH2D1A, SH3GL3, SH3TC1, SHD1, SHFM1, SHIvIT2,
SIAT1, SKB1, SKP2, SLA, SLC1A4, SLC20A1, SLC25A15, SLC25A5, SLC39A14, SLC39A6,
= SLC43A3, SLC4A2, SLC7A11, SLC7A6, SMA3, SMAD3, S/vIARCD3, SMOX, SMS,
SND1,
SNRPA, SNRPB, SNRPB2, SNRPE, SNRPF, SOD2, SOX4, SP140, SPANXC, SPARC, SPI1,
SRF, SRM,'SRRM1, SSA2, SSBP2, SSRP1, SSSCA1, STAG3, STAT1, STAT4, STAT5A,
STC1, STC2, STMN1, STOML2, SUI1, T3JAM, TACC1, TACC3, TAF5, TAGLN,
TAP1, TARP, TBCA, TCF12, TCF4, TCF7, TFDP2, TFPI, TFRC, TGFB1, TEA:N/117A,
T1MP 1,
=
=
CA 02631236 2014-07-22
TJP1, TIC2, TM4SF1, TM4SF2, TIvI4SF8, TM6SF1, TMEM2, TMEM22, TMSB 10, TMSNB,
TNFAIP3, INFAIP8, TNFRSF 10B, TNFRSF1A, TINTFRSF7, TN1X, TNP01, TOB1, TOMM20,
TOP2A, TOX, TPK1, TPM2, TRA@, TRA1, TRAM2, TR13@, TRD@, TRIM, TRIM14,
TRIM.22, TRIM28, TRTP13, TRPV2, TUBA3, TUBGCP3, TUFM, T1JSC3, TXN, TXNDC5,
UBASH3A, UBB, UBC, UBE2A, UBE2L6, UBE2S, UCHL1, UCK2, UCP2, UFD1L, UGCG,
UGDH, TJGT2B17, ULK2, UMPS, UNG, UROD, USP34, USP4, USP7, VASP, VAV1, VIM,
VLDLR, VWF, WARS, WASP1P, WBSCR20A, WBSCR20C, WHSC1, 'WNT5A, XP01,
ZAP128, ZAP70, ZFP36L I, ZNF32, ZNY335, 1NF593, ZNF'N1A1, or ZY.X.
The nucleic acid sequence of each of the listed genes is publicly available
through the
-rm
Genbank database. The gene sequences are also included as part of the HG-U133A
GeneChip
from Affymetrix, Inc.
"Resistant" or "resistance" as used herein means that a cell, a tumor, a
person, or a living
organism is able to withstand treatment, e.g., with a compound, such as a
chemotherapeutic agent
or radiation treatment, in that the treatment inhibits the growth of a cell,
e.g., a cancer cell, in
vitro or in a tumor, person, or living organism by less than 10%, 20%,.30%,
40%, 50%, 60%, or
70% relative to the growth of a cell not exposed to the treatment. Resistance
to treatment may be
determined by a cell-based assay that measures the growth of treated cells as
a function of the
cells' absorbance of an incident light beam as used to perform the NCI60
assays described
herein.. In this example, greater absorbance indicates greater cell growth,
and thus, resistance to
the treatment. A smaller reduction in growth indicates more resistance to a
treatment. By
"chemoresistant" or "chemoresistance" is meant resistance to a compound.
"Sensitive" or "sensitivity" as used herein means that a cell, a tumor, a
person, or a living
organism is responsive to treatment, e.g., with a compound, such as a
chemotherapeutic agent or
radiation treatment, in that the treatment inhibits the growth of a cell,
e.g., a cancer cell, in vitro
= or in a tumor, person, or living organism by 70%, 80%, 90%, 95%, 99% or
100%. Sensitivity to
treatment may be determined by a cell-based assay that measures the growth of
treated cells as a ,
function of the cells' absorbance of an incident light beam as used to perform
the NCI60 assays
described herein. In this example, lesser absorbance indicates lesser cell
growth, and thus,
26
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
sensitivity -Co the treatment. A greater reduction in growth indicates more
sensitivity to the
treatment. By "chemosensitive" or "chemosensitivity" is meant sensitivity to a
compound.
"Complement" of a nucleic acid sequence or a "complementary" nucleic acid
sequence as
used. herein refers to an oligonucleotide which is in "antiparallel
association" when it is aligned
with the nucleic acid sequence such that the 5' end of one sequence is paired
with the 3' end of
the other. Nucleotides and other bases may have complements and may be present
in
complementary nucleic acids. Bases not commonly found in natural nucleic acids
that may be
included in the nucleic acids of the present invention include, for example,
inosine and 7-
deazaguanine. "Complementarity" may not be perfect; stable duplexes of
complementary nucleic
acids may contain mismatched base pairs or unmatched bases. Those skilled in
the art of nucleic
acid technology can determine duplex stability empirically considering a
number of variables
including, for example, the length of the oligonucleotide, percent
concentration of cytosine and
guanine bases in the oligonucleotide, ionic st.cengthõ and incidence of
mismatched base pairs.
When complementary nucleic acid sequences form a stable duplex, they are said
to be
"hybridized" or to "hybrirli7e" to each other or it is said that
"hybridization" has occurred.
Nucleic acids are referred to as being "complementary" if they contain
nucleotides or nucleotide
homologues that can form hydrogen bonds according to Watson-Crick base-pairing
rules (e.g., G
with C, A with T or A with U) or other hydrogen bonding motifs such as for
example
diaminopurine with T, 5-methyl C with G, 2-thiothymidine with A, inosine with
C,
pseudoisocytosine with G, etc. Anti-sense RNA may be complementary to other
oligonucleotides, e.g., mR_NA.
"Biomarker" as used herein indicates a gene whose expression indicates
sensitivity or -
resistance to a treatment.
"Compound" as used herein means a chemical or biological substance, e.g., a
drug, a
protein, an antibody, or an oligonucleotide, which may be used to treat a
disease or which has
biological activity in vivo or in vitro. Preferred compounds may or may not be
approved by the
U.S. Food and Drug Administration (FDA). Preferred compounds include, e.g.,
chemotherapy
agents that may inhibit cancer growth. Preferred chemotherapy agents include,
e.g., Vincristine,
27
. = =
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
=
Cisplatin,.Azaguanine, Etoposide, Adriamycin, Aclarubicin, Mitoxantrone,
Mitomycin,
Paclitaxel, Gemcitabine, Taxotere, Dexamethasone, Ara-C, Methylprednisolone,
Methotrexate,
Bleornycin, Methyl-GAG, Carboplatin, 5-FU (5-FIuorouracil), MABTHERATm
(Rituximab), =
radiation, histone deacetylase (HDAC) inhibitors, and 5-Aza-2'-deoxycytidine
(Decitabine).
Exemplary radioactive chemotherapeutic agents include compounds containing
alpha emitters
= such as astatine-211, bismuth-212, bismuth-213, lead-212, radium-223,
actinium-225, and
thorium-227, beta emitters such as tritium, strontium-90, cesium-137, carbon-
11, nitrogen-13,
oxygen-15, fluorine-18, iron-52, cobalt-55, cobalt-60, copper-61, copper-62,
copper-64, zinc-62,
zinc-63, arsenic-70, arsenic-71, arsenic-74, bromine-76, bromine-79, rubidium-
82, yttrium-86,
zirconium-89, iridium-110, iodine-120, iodine-124, iodine-129, iodine-131,
iodine-125, xenon-
122, technetium-94m, teclmetium-94, technetiiim-99m, and technetium-99, or
gamma emitters
such as cobalt-60, cesium-137, and technetium-99m. Exemplary chemotherapeutic
agents also
include antibodies such as Alemtuzumab, Daclizumab, Rituximab (MABTHERATm),
Trastuzumab (BERCEPTINTm), Gemtuzumab, Ibritumomab, Edrecolomab, Tositumomab,
CeaVac, Epratuzumab, Mitumomab, Bevacizumab, Cetuximab, Edrecolomab,
Lintuzumab,
MDX-210, IGN-101, MDX-010, MAb, AME, ABX-EGF, EMT) 72 000, Apolizumab,
Labetuzumab, ior-ti, MDX-220, MRA, H-11 scFv, Oregovomab, hu3391 MAb, BZL,
Visilizumab, TriGem, TriAb, R3, MT-201, G-250, unconjugated, ACA-125, Onyvax-
105, CDP-
= 860, BrevaRex MAb, AR54, EMC-1C11, GlioMAb-H, Anti-LCG MAbs, MT-
103, KSB-
303, Therex, KW-2871, Anti-HIVII.24, Anti-PTHrP, 2C4 antibody, SGN-30, TRAIL-
RI MAb,
CAT, Prostate cancer antibody, H22xKi-4, ABX-MA1, Imuteran, and Monopharm-C.
Exemplary chemotherapeutic agents also include Acivicin; Aclarubicin;
Acodazole
Hydrochloride; Acronix' ie; Adozelesin; Adriamycin; Aldesleuicin; Altretamine;
Ambornycin; A.
metantrone Acetate; Aminoglutethimide; Amsacrine; Anastrozole; Anthramycin;
Asparaginase;
Asperlin; Azacitidine; Azetepa; Azotomycin; Batimastat; Benzodepa;
Bicalutamide; Bisantrene
Hydrochloride; Bisnafide Dimesylate; Bizelesin; Bleomycin Sulfate; Brequinar
Sodium;
Bropirimine; Busulfan; Cactinomycin; Calusterone; Camptothecin; Caracernide;
Carbetimer;
Carboplatin; Carrnustine; Carubicin Hydrochloride; Carzelesin; Cedefingol;
Chlorarnbucil;
28
.: = ' . =.
=
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
Cirolemycin;= Cisplatin; Cladribine; Combretestatin A-4; Crisnatol Mesylate;
Cyclophosphamide;
= Cytarabine; Dacarbazine; DACA (N- [2- (Dimethyl-amino) ethyl] acridine-4-
carboxarnide);
Dactinomycin; Daunorubicin Hydrochloride; Daunornycin;.Decitabine;
Dexormaplatin;
Dezaguanine; Dezaguanine Mesylate; Diaziquone; Docetaxel; Dolasatins;
Doxorubicin;
Doxorubicin Hydrochloride; Droloxifene; Droloxifene Citrate; Dromostanolone
Propionate;
Duazomycin; Edatrexate; Eflornithine Hydrochloride; Ellipticine; Elsamitrucin;
Enloplatin;
Enpromate; Epipropidine; Epimbicin Hydrochloride; Erbulozole; Esorubicin
Hydrochloride;
Estramustine; Estramustine Phosphate Sodium; Etanida7o1e; Ethiodized Oil I
131; Etoposide;
Etopo side Phosphate; Etoprine; Fadrozole Hydrochloride; Fazarabine;
Fenretinide; Floxuridine;
Fludarabine Phosphate; Fluorouracil; 5-FdLIMP; Flurocitabine; Fosquidone;
Fostrieein Sodium;
Gemcitabine; Gemcitabine Hydrochloride; Gold Au 198; Homocamptothecin;
Hydroxyurea;
Idarubicin Hydrochloride; Ifosfarnide; Ilmofosine; Interferon Alfa-2a;
Interferon Alfa-2b;
Interferon Alfa-nl; Interferon Alfa-n3; Interferon Beta-I a; Interferon Gamma-
I b; Iproplatin;
Irinotecan Hydrochloride; Lanreotide Acetate; Letrozole; Leuprolide Acetate;
Liarozole
Hydrochloride; Lometrexol Sodium; Lomustine; Losoxantrone Hydrochloride;
Masoprocol;
Maytansine; Mechlorethamine Hydrochloride; Megestrol Acetate; Melengestrol
Acetate;
Melphalan; Menogaril; Mercaptoptuine; Methotrexate; Methotrexate Sodium;
Metoprine;
Meturedepa; Mitindomide; Mitocarcin; Mitocromin; Mitogillin; Mitomalcin;
Mitomycin;
Mitosper; Mitotane; Mitoxantrone Hydrochloride; Mycophenolic Acid; Nocodazole;
Nogalamycin;Ormaplatin; Oxisuran; Paclitaxel; Pegaspargase; Peliomycin;
Pentamustine;
PeploycinSulfate; Perfosfamide; Pipobroma.n; Piposulfan; Piroxantrone
Hydrochloride;
Plicamycin; PlomeStane; Porfimer Sodium; Porfiromycin; Prednimustine;
Procarbazine
Hydrochloride; P-uromycin; Puromycin Hydrochloride; Pyrazofurin; Rhizoxin;
Rhizoxin D;
Riboprine; Rogletimide; Safmgol; Safingol Hydrochloride; Semustine;
Simtrazene; Sparfosate
Sodium; Sparsomycin; Spirogermanium Hydrochloride; Spirornustine; Spiroplatin;
Streptonigrin; Streptozocin; Strontium Chloride Sr 89; Sulofenur; Talisomycin;
Taxane; Taxoid;
Tecogalan Sodium; Tegafur; Teloxantrone Hydrochloride; Temoporfin; Teniposide;
Teroxirone;
Testolactone; Thiainiprine; Thioguanine; Thiotepa; Thymitaq; Tiazofurin;
Tirapazamine; =
29
=
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
Tomudex; TOP53; Topotecan Hydrochloride; Toremifen.e Citrate; Trestolone
Acetate;
Triciribine Phosphate; Trimetrexate; Trimetrexate Glucuronate; Triptorelin;
Tubulozole
Hydrochloride; Uracil Mustard; Uredepa; Vapreotide; Verteporfin; Vinblastine;
Vinblastine
Sulfate; VincristMe; Vincristine Sulfate; Vindesine; Vindesine Sulfate;
Vinepidine Sulfate;
Vinglycinate Sulfate; Vinleurosine Sulfate; Vinorelbine Tartrate; Vinrosidine
Sulfate;
Vinzolicline Sulfate; Vorozole; Zeniplatin; Zinostatin; Zorubicin
Hydrochloride; 2-
Chlorodeoxyadenosine; 2' Deoxyformycin; 9-aminocamptothecin; raltitrexed; N-
propargy1-5,8-
dideazafolic acid; 2ch1oro-2'-arabino-fluoro-2'-deoxyadenosine; 2-chloro-2'-
deoxyadenosine;
sni somycin; trichostatin A; hPRL-G129R; CEP-751; linomide; sulfur mustard;
nitrogen mustard
(naechlor ethamine); cyclophosphamide; melphalan; chlorarnbucil; ifosfamide;
busulfan; N-
methyl-Nnitrosourea (MNU); N, N'-Bis (2-chloroethyl)-N-nitrosourea (BCNU); N-
(2-
chloroethy1)-N' cyclohexYl-N-nitrosourea (CCNU); N- (2-chloroethyl)-M- (trans-
4-
methylcyclohexyl-N-nitrosourea (IvIeCCNU); N- (2-chloroethyl)-N'- (diethyl)
ethylphosphonate-
N-nitrosourea (fotemustine); streptozotocin; diacarbazine (DTIC);
mitozolomide; temozolomide;
thiotepa; mitomycin C; AZQ; adozelesin; Cisplatin; Carboplatin.; Ormaplatin;
Oxaliplatin;C1 -
973; DWA 2114R; .TM216; .TM335; Bis (platinum); tomudex; azacitidine;
cytarabine;
gemcitabine; 6-MercaptoPurine; 6-ThiogruanMe; Hypoxanthine; teniposide 9-amino
camptothecin; Topotecan; CPT-11; Doxorubicin; Daunomycin; Epirubicin;
darubicin;
mitoxantrone; losoxantrone; Dactinomycin (Actinomycin D); ainsacrine;
pyrazoloacridine; all-
trans retinol; 14-hydroxy-retro-retinol; all-trans retinoic acid; N- (4-
Hydroxyphenyl) retinarnide;
13-cis retinoic acid; 3-Methyl TTNEB; 9-cis retinoic acid; fludarabine (2-F-
ara-AMP); or 2-
chlorodeoxyadenosine (2-Cda).
Other chemotherapeutic agents include, but are not limited to, 20-pi-1,25
dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene;
adecypenol;
adozelesin; aldesleuldn; ALL-TK antagonists; altretamine; ambatnustine;
arnidox; amifostine;
arninolevulixiic acid; amrubicin; amsacrine; anagrelide; anastrozole;
andrographolide;
angiogenesis inhibitors; antagonist D; antagonist 0; antarelix; anti-
dorsalizing morphogenetic
protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston;
antisense
' 30
=
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis
regulators;
apurinic acid; ara-CDP-DL-PTBA; argininedeaminase; asulacrhie; atamestane;
atrimustine;
axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; a7a1yrosine;
baccatin UI
derivatives; balanol; batimastat; BCRJABL antagonists; benzochlorins;
benzoylstaurosporine;
beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFG-F
inhibitor;
bicalutatnide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A;
bizelesin; breflate;
bleomycin A2; bleomycin B2; bropirimine; budotitane; buthionine suIfoximine;
calcipotriol;
calphostin C; camptothecin derivatives (e.g., 10-hydroxy-camptothecin);
canarypox 11-2;
capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3;
CARN 700;
cartilage derived inhibitor; carzelesin; casein kinase inhibitors (1COS);
castanospermine;
cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost;
cis-porphyrin;
cladribine; clomifene analogues; clotrirnazole; collismycin A; collismycin B;
combretastatin A4;
combretastatin analogue; conagenin; crambescidin 816 ; crisnatol; cryptophycin
8; cryptophycin
A derivatives; cinacin. A; cyclopentanthraquinones; cycloplatam; cypemycin;
cytarabine
ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine;
dehydrodidemnin B;
Tdeoxycoformycin (DCF); deslorelin; dexifosfamide; dexrazoxane; dexverapamil;
diaziquone;
clidernnin. B; didox; diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol,
9-; dioxamycin;
diphenyl spiromustine; discoderraolide; docosanol; dolasetron; doxifluriciine;
droloxifene;
dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab;
eflorrithine;
elemene; emitefur; epirubicin; epothilones (A, .R = H; B, R = Me);
epithilones; epristeride;
estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole;
etoposide; etoposide
41-phosphate (etopofos); exemestane; fadrozole; fazarabine; fenretinide;
filgrastim; finasteride;
flavophidol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin
hydrochloride;
forfenimex; forrnestane; fostriecin; fotemustine; gadolinium texaphyrin;
gallium nitrate;
galocitabine; ganixelix; gelatinase inhibitors; gerircitabine; glutathione
inhibitors; hepsulfam;
heregulin; hexamethylene bisacetamide; homoharringtonine (HET); hypericin;
ibandronic acid;
idarubicin; idoxifene; idrarnantone; ilmofosine; ilomastat; imidazoacridones;
irniquimod;
irnmunostimulant peptides; insulin-like growth factor-I receptor inhibitor;
interferon agonists;
31
=
: = = = -
= = = =
= =
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
interferons; interleukins; iobenguane; iododoxorubicin; iponieanol, 4- ;
irinotecan; iroplact;
irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide;
kahalalide F;
lanaellarin-N triacetate; lanreotide; leinaraycin; lenograstim; lentinan
sulfate; leptolstatin;
letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide
+ estrogen +
progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue;
lipophilic
disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7;
lobaplatin; lombricine;
lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan;
lutetium texaphyrin;
lysofylline; lytic peptides; maytansine; marmostatin A; marimastat;
masoprocol; maspin;
matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril;
merbarone; meterelin;
methioninase; metoclopramide; MIF inhibitor; ifepristone; miltefosine;
nairimostim; mismatched
double stranded RNA; mithracin; rnitoguazone; mitolactol; mitornyein
analogues; mitonafide;
mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene;
molgramostim;
monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A +
myobacterium
cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple
tumor suppressor 1-
based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell
wall extract;
m.yriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin;
nagrestip; naloxone +
pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin;
neridronic acid; neutral
endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide
antioxidant; nitrullyn;
. 06-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;
ondansetron;
ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone;
oxaliplatin; oxaunomycin;
paclitaxel analogues; paclitaxel derivatives; palauamine; palraitoylrhizcadn;
pamidronic acid;
panaxytriol; panornifene; parabactin; pazelliptine; pegaspargase; peldesine;
pentosan polysulfate
sodium; pentostatin; pentrozole; perflubron; perfosfarnide; perillyl alcohol;
phenazinomycin;
phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride;
pirarubicin;
piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum
complex; platinum
compounds; platinum-triamine complex; podophyllotoxin; porftmer sodium;
porfiromycin;
propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based
immune
modulator; protein lcinase C inhibitor; protein kinase C inhibitors,
microalgal; protein tyrosine
32
=
. . . = .
= ==
= .=
= =
CA 02631236 2008-05-26
WO 2007/072225
PCT/IB2006/004048
phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins;
pyrazoloacridine;
pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;
raltitrexed; ramosetron;
ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP
inhibitor; retelliptine
demethylated; rhenium Re 186 etidronate; rhiz. oxin; ribozynaes; RU
retinamide;.rogletimide;
rohitukine; romurtide; roquinimex; rubiginone B 1; ruboxyl; safingol;
saintopin; SarCNU;
sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived
inhibitor 1; sense
oligonucleotides; signal transduction inhibitors; signal transduction
modulators; single chain
antigen binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium
phenylacetate;
solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D;
spiromustine;
splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell
division inhibitors; =
stipiamide; stronaelysin inhibitors; sulfinosine; superactive vasoactive
intestinal peptide
antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans;
tallimustine;
tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur;
tellurapyryliurn;
telomerase inhibitors; temoporfin; temozolomide; teniposide;
tetrachlorodecaoxide; tetrazomine;
thsliblastine; thalidomide; thiocoraline; tbrombopoietin; thrombopoietin
mimetic; thymalfasin;
thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin
ethyl etiopurpurin;
tirapazamine; titanocene dichloride; topotecan; topsentin; toremifene;
totipotent stem cell factor;
translation inhibitors; tretinoin; triacetyluridine; triciribine;
trimetrexate; triptorelin; tropisetron;
turosteride; tyrosine kinase inhibitors; tyrphostins; LTBC inhibitors;
ubenimex; urogenital sinus-
derived growth inhibitory factor; urokinase receptor antagonists; vapreotide;
variolin B; vector
system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin;
vinorelbine;
vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and
zinostatin stimalamer.
To "inhibit growth" as used herein means causing a reduction in cell growth
in.vivo or in
vitro by, e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% or
more, as
evident by a reduction in the size or number of cells exposed to a treatment
(e.g., exposure to a
compound), relative to the size or number of cells in the absence of the
treatment. Growth
inhibition may be the result of a treatment that induces apoptosis in a cell,
induces necrosis in a
cell, slows cell cycle progression, disrupts cellular metabolism, induces cell
lysis, or induces
33
=
CA 02631236 2014-07-22
some either mechanism that reduces the size or number of cells.
"Marker gene" or "biomarker gene" as used herein means a gene in a cell the
expression of which correlates to sensitivity or resistance of the cell (and
thus the patient from
which the cell was obtained) to a treatment (e.g., exposure to a compound).
"Microarray" as used herein means a device employed by any method that
quantifies
one or more subject oligonucleotides, e.g., DNA or RNA, or analogues thereof,
at a time. One
exemplary class of microarrays consists of DNA probes attached to a glass or
quartz surface.
For example, many microarrays, including those made by Affymetrix, use several
probes for
determining the expression of a single gene. The DNA microarray may contain
oligonucleotide
probes that may be, e.g., full-length cDNAs complementary to an RNA or cDNA
fragments
that hybridize to part of an RNA. Exemplary RNAs include mRNA, miRNA, and
miRNA
precursors. Exemplary microarrays also include a "nucleic acid microarray"
having a
substrate-bound plurality of nucleic acids, hybridization to each of the
plurality of bound
nucleic acids being separately detectable. The substrate may be solid or
porous, planar or non-
planar, unitary or distributed. Exemplary nucleic acid microarrays include all
of the devices so
called in Schena (ed.), DNA Microarrays: A Practical Approach (Practical
Approach Series),
Oxford University Press (1999); Nature Genet. 21(1)(suppl.):1-60 (1999);
Schena (ed.),
Microarray Biochip: Tools and Technology, Eaton Publishing
Company/BioTechniques Books
Division (2000). Additionally, exemplary nucleic acid microarrays include
substrate-bound
plurality of nucleic acids in which the plurality of nucleic acids are
disposed on a plurality of
beads, rather than on a unitary planar substrate, as is described, inter alia,
in Brenner et al.,
Proc. Natl. Acad. Sci. USA 97(4):1665-1670 (2000). Examples of nucleic acid
microarrays
may be found in U.S. Pat. Nos. 6,391,623, 6,383,754, 6,383,749, 6,380,377,
6,379,897,
6,376,191, 6,372,431, 6,351,712, 6,344,316, 6,316,193, 6,312,906, 6,309,828,
6,309,824,
6,306,643, 6,300,063, 6,287,850, 6,284,497, 6,284,465, 6,280,954, 6,262,216,
6,251,601,
6,254,518, 6,263,287, 6,251,601, 6,238,866, 6,228,575, 6,214,587, 6,203,989,
6,171,797,
6,103,474, 6,083,726, 6,054,274, 6,040,138, 6,083,726, 6,004,755, 6,001,309,
5,958,342,
5,952,180, 5,936,731, 5,843,655, 5,814,454, 5,837,196, 5,436,327, 5,412,087,
5,405,783.
34
CA 02631236 2014-07-22
Exemplary microarrays may also include "peptide microarrays" or "protein
microairays"
having a substrate-bound plurality of polypeptides, the binding of a
oligonucleotide, a peptide, or
a protein to each of the plurality of bound polypeptides being separately
detectable. Alternatively,
the peptide naicroarray, may have a plurality of binders, including but not
limited to monoclonal
antibodies, polyclonal antibodies, phage display binders, yeast 2 hybrid
binders, aptamers, which
can specifically detect the binding of specific oligonucleotides, peptides, or
proteins. Examples
of peptide arrays may be found in WO 02/31463, WO 02/25288, WO 01/94946, WO
01/88162,
WO 01/68671, WO 01/57259, WO 00/61806, WO 00/54046, WO 00/47774, WO 99/40434,
WO
99/39210, WO 97/42507 and U.S. Pat. Nos. 6,268,210, 5,766,960, 5,143,854.
"Gene expression" as used herein means the amount of a gene product in a cell,
tissue,
organism, or subject, e.g., amounts of DNA, RNA, or proteins, amounts of
modifications of
DNA, RNA, or protein, such as splicing, phosphorylation, acetylation, or
methylation, or
amounts of activity of DNA, RNA, or proteins associated with a given gene.
"NCI60" as used herein means a panel of 60 cancer cell lines from lung, colon,
breast,
ovarian, leukemia, renal, melanoma, prostate and brain cancers including the
following cancer
cell lines: NSCLC_NCIE123, NSCLC_NaH522, NSCLC_A549ATCC, NSCLC_EKVX,
NSCLC NCIH226, NSCLC NCIH332M, NSCLC_H460, NSCLC_HOP62, NSCLC_H0P92,
COLON HT29, COLON_HCC-2998, COLON HCT116, COLON_SW620,
COLON_COL0205, COLON_HCT15, COLON_KM12, BREAST_MCF7, .
BREAST_MCF7ADRr, BREAST_MDAMB231, BREAST_HS578T, BREAST_MDAMB435,
BREAST_MDN, BREAST_BT549, BREAST_T47D, OVAR_OVCAR3, OVAR_OVCAR4,
OVAR OVCAR5, OVAR_OVCAR8, OVAR_IGROV1, OVAR_SKOV3, LEUK_CCRFCEM,
LEUK_K562, LEUK_MOLT4, LEUK HL60, LEUK_RPM18266, LEUK_SR, RENAL_U031,
RENAL_SN12C, RENAL_A498, RENAL_CAKI1, RENAL_RXF393, RENAL_7860,
RENAL_ACEIN, RENAL_TK10, MELAN_LOXIMVI, MELAN_MALlVfE3M,
MELAN_SKMEL2, MELAN_SKMEL5, MELAN_SKMEL28, MELAN_Ml 4,
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
MELAN UACC62, MELA_N_UACC257, PROSTATE: PC3, PROSTATE_DU145,
CNS_SNB19, CNS_SNB75, CNS_U251, CNS SF268, CNS SF295, and CNS SF539.
= "Treatment" or "medical treatment'.' means administering to a.subject or
living organism
or exposing to a cell or tumor a compound (e.g., a drug, a protein, an
antibody, an
oligonucleotide, a chemotherapeutic agent, and a radioactive agent) or some
other form of
medical intervention used to treat or prevent cancer or the symptoms of cancer
(e.g., cryotherapy
and radiation therapy). Radiation therapy includes the administration to a
patient of radiation
generated from sources such as particle accelerators and related medical
devices that emit X- .
radiation, gamma radiation, or electron (Beta radiation) beams. A treatment
may further include
surgery, e.g., to remove a tumor from a subject or living organism.
Other features and advantages of the invention will be apparent from the
following
Detailed Description, the drawings, and the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 depicts an illustration of the method Of identifying biomarkers and
predicting
= patient sensitivity to a medical treatment. The method has an in vitro
component where the
growth inhibition of a compound or medical treatment is measured on cell lines
(6 of the 60 cell
lines tested are shown). The gene expression is measured on the same cell
lines without
compound treatment. Those genes that have a correlation above a certain cutoff
(e.g., a preffered
cutoff of 0.3, in which a correlation coefficient equal to or greater than the
cutoff of 0.3 is
deemed statistcally significant by, e.g., cross-validation) to the growth
inhibition are termed
marker genes and the expression of those genes in vivo, e.g., may predict the
sensitivity or
resistance of a patient's cancer to a compound or other medical treatment. The
in vivo component
is applied to a patient to determine whether or not the treatment will be
effective in treating
disease in the patient. Here, the gene expression in cells of a sample of the
suspected disease
tissue (e.g., a tumor) in the patient is measured before or after treatment.
The activity of the
marker genes in the sample is compared to a reference population of patients
known to be
sensitive or resistant to the treatment. The expression of marker genes in the
cells of the patient
36
. = = .
. .
. =
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
known to be expressed in the cells of reference patients sensitive to the
treatment indicates that
the patient to be treated is sensitive to the treatment and vice versa. Based
on this comparison the
patient is predicted to be sensitive or resistant to treatment with the
compound.
Figure 2 depicts the treatment sensitivity predictions for a 5-year-old
American boy with
a brain tumor. The subject had surgery to remove the tumor and, based on the
analysis of gene
expression in cells from a sample of the tumor, the subject was predicted to
be chemosensitive to
ten chemotherapy drugs. The subject received Vincristine and Cisplatin and
survived.
Figure 3 depicts the treatment sensitivity predictions for a 7-month-old
American girl
with a brain tumor. The subject had surgery to remove the tumor, and based on
the analysis of
gene expression in cells from a sample of the tumor, the subject was predicted
to be
chemoresistant to twelve chemotheraphy drugs. The subject received Vincristine
and Cisplatin,
but passed away 9 months later.
Figure 4 depicts the survival rate of 60 brain cancer patients divided into a
group
predicted to be chemosensitive to Cisplatin and a group predicted to be
chemoresistant to
Cisplatin. All patients received Cisplatin after surgery.
Figure 5 depicts the survival rate of 56 lymphoma patients divided into a
group predicted
to be chemosensitive to Vincristine and Adriamycin and a group predicted to be
chemoresistant.
All patients received Vincristine and Adriarnycin.
Figure 6 depicts the survial rate of 19 lung cancer patients divided into a
group predicted
to be chemosensitive to Cisplatin and a group predicted to be chemoresistant.
All patients
received Cisplatin.
Figure 7 depicts the survival rate of'14 diffuse large-B-cell lymphoma (DLBCL)
patients
divided into a group predicted to be chemosensitive to the drug combination R-
CHOP and a
group predicted to be chemoresistant. All patients were treated with R-CHOP.
Figure 8 depicts the predictions of sensitivity or resistance to treatment of
a patient
diagnosed with DLBCL. Various drug combinations and radiation therapy are
considered. The.
drug combinations (indicated by abbreviations) are those commonly used to
treat DLBCL.
Figure 9 depicts the survival rate of 60 brain cancer patients divided into a
group = =
37
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
=
predicted to be sensitive to radiation treatment and a group predicted to be
resistant. All patients
= were treated with radiation.
Figure 10 depicts the survival rate of 60 brain cancer patients divided into a
group
predicted to be sensitive to radiation treatment and a group predicted to be
resistant. All patients
were treated with radiation. Gene biomarkers used in predicting radiation
sensitivity or
resistance were obtained using the correlation of the median gene expression
measurement to
cancer cell growth as opposed to the median of the correlations as employed in
Figure 9.
= DETAILED DESCRIPTION
= The invention features methods for identifying biomarkers of treatment
sensitivity, e.g.,
chemosensitivity to compounds, or resistance, devices that include the
biomarkers, kits that
include the devices, and methods for predicting treatment efficacy in a
patient (e.g., a patient
diagnosed with cancer). The kits of the invention include microarrays having
oligonucleotide
probes that are biomsrkers of sensitivity or resistance to treatment (e.g.,
treatment with a
chemotherapeutic agent) that hybridize to nucleic acids derived from or
obtained from a subject
and instructions for using the device to predict the sensitivity or resistance
of the subject to the
treatment. The invention also features methods of using the microaxrays to
determine whether a
subject, e.g., a cancer patient, will be sensitive or resistant to treatment
with, e.g., a chemotherapy
agent. Also featured are methods of identifying gene biomarkers of sensitivity
or resistsnce to a
medical treatment based on the correlation of gene biomarker expression to
treatment efficacy,
e.g., the growth inhibition of cancer cells. Gene biomarkers that iden.tify
subjects as sensitive or
resistant to a treatment may also be identified within patient populations
already thought to be
sensitive or resistant to that treatment. Thus, the methods, devices, and kits
of the invention can
be used to identify patient -subpopulations that are responsive to a treatment
thought to be
ineffective for treating disease (e.g., cancer) in the general population.
More generally, cancer
patient sensitivity to a compound or other medical treatment may be predicted
using biomarker
gene expression regardless of prior knowledge about patient responsiveness to
treatment. The
= method according to the present invention can be implemented using
software that is run on an
38 =
= =
. .
- :
= =
. .
=
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
apparatus for measuring gene expression in connection, with a microarray. The
microarray (e.g. a
DNA microatray), included in a kit for processing a tumor sample from a
subject, and the =
apparatus for reading the micro array and turning the result into a chemo
sensitivity profile for the
subject may be used to implement the methods of the invention.
Microarrays Containing Oligonucleotide Probes
The microarrays of the invention include one or more oligonucleotide probes
that have
nucleotide sequences that are identical to or complementary to, e.g., at least
5, 8, 12, 20, 30, 40,
60, 80, 100, 150, or 200 consecutive nucleotides (or nucleotide analogues) of
the biomarker
genes listed below. The oligonucleotide probes may be, e.g., 5-20, 25, 5-50,
50-100, or over 100
nucleotides long. The oligonucleotide probes may be deoxyribonucleic acids
(DNA) or
ribonucleic acids (RNA). Consecutive nucleotides within the oligonucleotide
probes (e.g., 5-20,
25, 5-50, 50-100, or over 100 consecutive nucleotides), which are used as gene
biomarkers of
chemosensitivity, may also appear as consecutive nucleotides in one or more of
the genes
described herein beginning at or near, e.g., the first, tenth, twentieth,
thirtieth, fortieth, fiftieth,
sixtieth, seventieth, eightieth, ninetieth, hundredth, hundred-fiftieth, two-
hundredth, five-
hundredth, or one-thousandth nucleotide of the genes listed in Tables 1-21 or
below. Column
List_2006 of Tables 1-21 indicates the preferred gene biomarkers for the
compound lists.
Column List_Preferred of Tables 1-21 indicates the most preferred gene
biomarkers. Colrimn
List 2005 of Tables 1-21 indicates additional biomarkers employed in Examples
1-8. Column
Correlation of Tables 1-21 indicates the correlation coefficient of the
biomarker gene expression
to cancer cell growth inhibition. The following combinations of gene
biomarkers have been used
to detect a subject's sensitivity to the indicated treatment:
=
a) One or more of the gene sequences SFRS3, CCT5, RPL39, SLC25A5, UBE2S,
EEF1A1,
RPLP2, RPL24, RPS23, RPL39, RPL18, NCL, RPL9, RPL10A, RPS10, ElF3S2, SHFM1,
RPS28, REA, RPL36A, GAPD, HNRPA1, RPS11, HNRPA1, LDHB, RPL3, RPL11, MRPL12,
RPL18A, COX7B, and RPS7, preferably gene sequences UBl3, RPS4X, S100A4,
NDUFS6,
39
=
. _
=
. =
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
B2M, C14orf139, MAN1A1,'SLC25A5, RPL10, RPL12, ElF5A, RPL36A, SUB, BLMEI,
CTBP1, TBCA, MDH2, and DXS9879E, and most preferably gene sequences RPS4X,
SIO0A4, =
NDUFS6, CI4orfl39, SLC25A5, RPL10, RPL12, EIF5A, RPL36A, BLMH, CTBP1, TBCA,
MDH2, and. DXS9879E, whose expression indicates chemosensitivity to
Vincristine.
b)
One or more of the gene sequences B2M, ARFIGDLB, FTL, NCL, MSN, SNRP. F,
XP01, =
LDHB, SNRPF, GAPD, PTPN7, ARHGDLB, RPS27, IF116, C5orf13, and HCLS1,
preferably
gene sequences Cl QR1, HCLS1, CD53, SLA, PTPN7, PTPRCAP, ZNFN1A1, CENTB1,
PTPRC, IFI16, ARHGEF6, SEC31L2, CD3Z, GZMB, CD3D, MAP4K1, GPR65, PRF1,
ARHGAP15, TM6SFI, and TCF4, and most preferably gene sequences Cl QR1, SLA,
PTPN7,
ZNFN1A1, CEN __ 1131, LE116, ARHGEF6, SEC31L2, CD3Z, GZMB, CD3D, MAP4K1,
GPR65,
PRF I, ARHGAP15, TM6SF1, and TCF4, whose expression indicates chemosensitivity
to
Cisplatin.
c)
One or more of the gene sequences PRPS1, DDOST, B2M, SPARC, LGALS I, CBFB,
=
SNRPB2, MCA.M, MCAM, ElF2S2, HPRT1, SRM, FKBP1A, GYPC, UROD, MSN, HNRPA1,
SND1, COPA, MAPRE1, EIF3S2, ATP1B3, EMP3, ECM1, ATOX1, NARS, PGKI, OK/SW-
c1.56, FN1, EEF1A1, GNAI2, PRPS1, RPL7, PSMB9, GPNIV113, PPP1R11, MLA, RAB7,
and SMS, preferably gene sequences MSN, SPARC, VIM, SRM, SCARBI, SIAT1,
CUGBP2,
GAS7, ICAM1, WASPIP, ITM2A, PALM2-AKAP2, ANPEP, PTPNS I, MPP1, LNK, FCGR2A,
EMP3, RUNX3, EVI2A, BTN3A3, LCP2, BCHE, LY96, LCP1, IF116, MCAM, MEF2C,
SLC1A4, BTN3A2, FYN, FN1, C1orf38, CHS1, CAPN3, FCGR2C, TN1K, AMPD2, SEPT6,
RAFTLIN, SLC43A3, RAC2, LPXN, 0K1P-1, FLJ10539, FLJ35036, DOCK10, TRPV2,
1PRG28, LEF1, and ADAMTS1, and most preferably gene sequences SRM, SCARB1,
SIAT1,
CUGBP2, ICAM1, WASPIP, ITM2A, PALM2-AKAP2, PTPNS I, MPP I, LNK, FCGR2A,
RUNX3, EV12A, BTN3A3, LCP2, BCHE, LY96, LCP1, IF116, MCAM, MEF2C, SLC1A4,
FYN, C1orf38, CHS1, FCGR2C, TNIK, AMPD2, SEPT6, RAFTL1N, SLC43A3, RAC2, LPXN,
CKIP-1, FL310539, FLJ35036, DOCK10, TRPV2, IFRG28, LEFT, and ADA_MTS1, whose
. =
=
).. = -
=
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
expression indicates chemosensitivity to Azaguanine.
d) One or more of the gene sequences B2M, MYC, CD99, RPS24, PPIF, PBEFI,
and
ANP32B, preferably gene sequences CD99, ENSIG1, LAPTM5, PRG1, MUFI, HCLS1,
CD53,
SLA, SSBP2, GN135, MENG, GMFG, PSMB9, EV12A, PTPN7, PTGER4, CXorf9, PTPRCAP,
ZNEN1A1, CENTB1, PTPRC, NAPILl, HLA-DRA, 1E116, CORO1A, ARHGEF6, PSCDBP,
SELPLG, LAT, SEC31L2, CD3Z, SH2D1A, GZMB, SCN3A, ITK, RAFTLIN, DOCK2, CD3D,
RAC2, ZAP70, GPR65, PRF1, ARHGAP15,NOTCH1, and UBASH3A, and most preferably
gene sequences CD99, INSIG1, PRG1, MUF1, SLA, SSBP2, GNB5, MENG, PSMB9, EVI2A,
PTPN7, PTGER4, CXorf9, ZNFN1A1, CENTB1, NAPILl, HLA-DRA, lFI16, ARHGEF6,
PSCDBP, SELPLG, LAT, SEC31L2, CD3Z, SH2D1A, GZMB, SCN3A, RAFTL1N, DOCK2,
CD3D, RAC2, ZAP70, GPR65, PRF1, ARHGAP15, NOTCH1, and LTBASH3A, whose
expression indicates chemosensitivity to Etoposide.
e) One or more of the gene sequences KTAA0220, B2M, TOP2A, CD99, SNRPE,
RPS27,
HNRPA1, CBX.3, ANP32B, HNRPA1, DDX5, PPIA, SNRPF, and USP7, preferably gene
sequences CD99, LAPTM5, ALDOC, HCLS1, CD53, SLA, SSBP2, IL2RG, GMFG, CXorf9,
RHOH, PTPRCAP, ZNENIA1, CENTB1, TCF7, CD1C, MAP4K1, CD1B, CD3G, PTPRC,
CCR9, CORO1A, CXCR4, ARHGEF6, HEM1, SELPLG, LAT, SEC31L2, CD3Z, SH2D1A,
CD1A, LAIR1, ITK, TRB@, CD3D, WBSCR20C, ZAP70, IF144, GPR65, AlF1, ARHGAP15,
NARF, and pACAP, and most preferably gene sequences CD99, ALDOC, SLA, SSBP2,
IL2RG,
CXorf9, RHOH, ZNENIA1, CENTB1, 6D1C, MAP4K1, CD3G, CCR9, CXCR4, ARHGEF6,
SELPLG, LAT, SEC31L2, CD3Z, SH2D1A, CD1A, LAIR1, TRB@, CD3D, WBSCR20C,
ZAP70, IF144, GPR65, AIF1, ARHGAP15, NARF, and PACAP, whose expression
indicates
chemosensitivity to Adriamycin.
f) One or more of the gene sequences RPLP2, LA1VIR1,.RPS25, EIF5A, TUFM,
IINRPA1,
RPS9, MYB, LAMR1, ANP32B, 1INRPA1, HNRPA1, EIF4B, HMGB2, RPS15A, and RPS7,
41
=
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
preferably gene sequences RPL12, RPL32, RPLP2, MYB, ZNIN1A1, SCAN, STAT4,
SP140,
AMPD3, TNFAIP8, DDX18, TAF5, FBL, RPS2, PTPRC, DOCK2, GPR65, HOXA9,
FL512270, and HNRPD, and most preferably gene sequences RPL12, RPLP2,
MYB,..ZNFN1A1,
SCAP I, STAT4, SP140, A.MPD3, TNFA1P8, DDX18, TAF5, RPS2, DOCK2, GPR65, HOXA9,
FLJ12270, and HNRPD, whose expression indicates chem.osensitivity to
Aclarubicin.
g) One or more of the gene sequences ARHGEF6, B2M, TOP2A, TOP2A, ELA2B,
PTMA,
LMNB1, TNFRSF1A, NAP11,1, B2M, BNRPA1, RPL9, C5orf13, NCOR2, ANP32B, OK/SW-
c1.56, TLTBA3, HMGN2, PRPS I, DDX5, PRG1, PPIA, G6PD, PSMB9, SNRPF, and MAP
1B,
preferably gene sequences PGAM1, DPYSL3, ENSIG1, GJA1, BNIP3, PRGI, G6PD,
BASP1,
PLOD2, LOXL2, SSBP2, C1orf29, TOX, STC1, TNFRSF1A, NCOR2, NAP1L1, L0C94105,
COL6A2, ARHGEF6, GATA3, TFPI, LAT, CD3Z, AF1Q, MAP1B, PIPRC, PRKCA-, TRIM22,
CD3D, BCATI, 1F144, CCL2, RAB31, CUTC, NAP1L2, NME7, FLJ21159, and COL5A2, and
most preferably gene sequences PGAM1, DPYSL3, INSIG1, GJA1, BNIP3, PRGI, G6PD,
PLOD2, LOXL2, SSBP2, C1orf29, TOX, STC1, TNERSF1A, NCOR2, NAPILl, LOC94105,
ARHGEF6, GATA3, TFPI, LAT, CD3Z, AF1Q, MAP IB, TRIM22, CD3D, BCAT1, IF'I44,
CUTC, NAP1L2, NME7, FLJ21159, and COL5A2, whose expression indicates
chemosensitivity
to Mitoxantrone.
h) One or more of the gene sequences GAPD, GAPD, GAPD, TOP2A, S Ull, TOP2A,
FTL,
HNRPC, TNFRSF1A, SHC1, CCT7, P4HB, CTSL, DDX5, G6PD, and SNRPF, preferably
gene
sequences STC1, GPR65, DocKio, COL5A2, FAM46A, and L0054103, and most
preferably
gene sequences STC1, GPR65, DOCK10, COL5A2, FAM46A, and L0054103, whose
expression indicates chemosensitivity to Mitomyein.
i) One or more of the gene sequences RPS23, SFRS3, KIAA0114, RPL39, SFRS3,
L0051035, RPS6, EXOSC2, RPL35, IFRD2, SMN2, EEF1A1, RPS3, RPS18, and RPS7,
preferably gene sequences RPL10, RPS4X, NUDC, RALY, DKC1, DKFZP564C186, PRP19,
42
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
RAB9P40, HSA9761, GMDS, CEP I, 1L13RA2, MAGEB2,
ALMSI, GPR65, .
FLJ10774, NOL8, DAZAP1, SLC25A15, PAF53, DXS9879E, PITPNC1, SPANXC, and
KIAA1393, and most preferably RPLIO, RPS4X,1\TUDC, DKC1, DKFZP564C186, PRP19,
RAB9P40, HSA9761, GMDS, CEP1,1L13RA2, MAGEB2, H.MGN2, ALMS', GPR65,
FLJ10774, NOL8, DAZAP1, SLC25A15, PAF53, DXS9879E, PITPNC1, SPANXC, and
KIAA1393, whose expression indicates chemosensitivity to Paclitaxel.
j) One or more of the gene sequences CSDA, LAMR1, and TUBA3, preferably
gene
sequences PFN1, PGAMI, K-ALPHA-1, CSDA, UCHL1, PWP1, PALM2-AKAP2,
TNERSF1A, ATP5G2, AF1Q, NME4, and FHOD1, and most preferably gene sequences
PFN1,
PGAM1, K-ALPHA- I, CSDA, UCHL1, PWP1, PALM2-AKAP2, TNFRSF1A, ATP5G2,
AF I Q, NME4, FHODI, whose expression indicates chemosensitivity to
Gemcitabine.
k) One or more of the gene sequences RPS23, SFRS3, KIAA0114, SFRS3, RPS6,
DDX39,
and RPS7, preferably gene sequences ANP32B, GTF3A, RR.M2, TRIM14, SKP2,
TRIP13,
RFC3, CASP7, TXN, MCM5, PTGES2, OBFC1, EPB41L4B, and CALML4, and most
preferably gene sequences ANP32B, __ RRM2, TRIM14, SKP2, TR1P13, RFC3,
CASP7,
TXN, MCM5, PTGES2, OBFC1, EPB41L4B, and CALML4, whose expression indicates
chemosensitivity to Taxotere.
1) One
or more of the gene sequences IL2RG, H1FX, RDBP, ZAP70, CXCR4, TM4SF2,
ARHGDIB, CDA, CD3E, STMNI, GNA15, AXL, CCND3, SA _______________________ I Bl,
EIF5A, LCK, NICX2-5,
LAPTM5, IQGAP2, FLIT, ElF3S5, TRB, CD3D, HOXB2, GATA3, HMGB2, PSMB9, ATP5G2,
CORO IA, ARHGDIB, DRAP I, PTPRCAP, RHOH, and ATP2A3, preferably gene sequences
IFITM2, UBE2L6, LAPTM5, USP4, ITM2A, ITGB2, ANPEP, CD53,M2RG, CD37,
GPRASP1, PTPN7, CXorf9, RHOH, GIT2, ADORA2A, ZNFN1A1, GNA15, CEP1, TNFRSF7,
MAP4K1, CCR7, CD3G, PTPRC, ATP2A3, UCP2, CORO1A, GATA3, CDKN2A,
TARP, LAIR1, SH2D1A, FLIL SEPT6, HA-1, CREB3L1, ERCC2, CD3D, LST1, AIF1, ADA,
43
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
DATF I, ARHGAP15, PLAC8, CECR1, LOC81558, and EILD2, and most preferably gene
sequences IFITM2, UBE2L6, USP4, ITM2A, IL2RG, GPRASP1, PTPN7, CXorf9, RHOH,
GIT2, ZNFN1A1, CEP1, TNFRSF7, MAP4K1, CCR7, CD3G, ATP2A3, UCP2, GATA3,
CDKN2A, TARP, LAIR.1, SH2D1A, SEPT6, HA-1, ERCC2, CD3D, LST1, ALF I , ADA,
DATF1, ARHGAP15, PLAC8, CECR1, LOC81558,,and EI-ID2, whose expression
indicates
chemosensitivity to Dexamethasone.
m) One or more of the gene sequences TM4SF2, ARHGDIB, ADA, H2AFZ, NAP1L1,
CCND3, FABP5, LAMR1, REA, MCM5, SNRPF, and USP7, preferably gene sequences
ITM2A, RHOH, PRIM1, CENTB1, GNA15, NAP1L1, ATP5G2, GATA3, PRKCQ, SH2D1A,
SEPT6, PTPRC, NME4, RPL13, CD3D, CD1E, ADA, and FHOD1, and most preferably
gene
sequences ITM2A, RHOH, PRIM1, CENTB1,NAP1L1, ATP5G2, GATA3, PRKCQ, SH2D1A,
SEPT6, NME4, CD3D, CD 1E, ADA, and FHODI, whose expression indicates
chemosensitivity
to Ara-C.
n) One or more of the gene sequences LGALS9, CD7, IL2RG, PTPN7, ARHGEF6,
CENTB1, SEPT6, SLA, LCP1, IFITM1, ZAP70, CXCR4, TM4SF2, ZNF91, ARHGDIB,
ITDP2, ADA, CD99, CD3E, CD1C, STMN1, CD53, CD7, GNA15, CCND3, MAZ, SATB1,
ZNF22, ABS. AWL MYB, LCK, C5orf1.3, NKX2-5, ZNFN1A1, STAT5A, CHI3L2, LAPTM5,
MAP4K1, DDX11, GPSM3, TRB, CD3D, CD3G, PRKCB1, CDIE, HCLS1, GATA3, TCF7,
RHOG, CDW52, IEVIGB2, DGKA, ITGB2, PSMB9, IDH2, AES, MCM5, NUCB2, CORO1A,
ARHGD1B, PiPRCAP, CD47, RHOH, LGALS9, and ATP2A3, preferably gene sequences
CD99, SRRM1, ARHGDIB, LAPTM5, VWF, ITM2A, ITGB2, LGALS9, INPP5D, SATB1,
CD53, TFDP2, SLA, IL2RG, MENG, CD37, GMFG, SELL, CDW52, LRMP, ICAM2, RIMS3,
PTPN7, ARHGAP25, LCK, CXorf9, RHOH, PTPRCAP, GIT2, ZNFN1A1, CENTB1, LCP2,
SPI1, GNA15, GZMA, CEP1, BLM, CD8A, SCAP1, CD2, CDIC, TNFRSF7, VAV1,
MAP4K1, CCR7, C6orf32, ALOX15B, BRDT, CD3G, PTPRC, LTB, ATP2A3, NVL,
RASGRP2, LCP1, COROIA, CXCR4, PRKD2, GATA3, TRA@, PRKCB1, HEW.,
44
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
KIAA0922, TARP, SEC31L2, PRKCQ, SH2D1A, CHRNA3, CD1A, LST1, LAIR?,
CACNAI G, TRB@, SEPT6, HA-1, DOCIC2, CD3D, TRD@, T3JAM, FNBP1, CD6, AlFI,
FOLH1, CDI E, LY9, UGT2B17, ADA, CDKL5, TRIM, EVL, DATFI, RGC32, PRKCH,
ARHGAP15, NOTCH?, BIN2, SEMA4G, DPEP2, CECRI, BCL11B, STAG3, GALNT6,
UBASH3A, PHEMX, FLJ13373, LEF1, IL21R, MGC17330, AKAP13, ZNF335, and G1MAP5,
and most preferably gene sequences CD99, ARHGDIB, VWF, ITM2A, LGALS9, INPP5D,
SATB1, TFDP2, SLA, 1L2RG, MFNG, SELL, CDW52, LRMP, ICAM2, RIMS3, PTPN7,
ARHGAP25, LCK, CXorf9, RHOH, GIT2, ZNFN1A1, CENTB1, LCP2, SPII, GZMA, CEP1,
CD8A, SCAP1, CD2, CD IC, TNFRSF7, VAV1, MAP4K1, CCR7, C6orf32, ALOX15B, BRDT,
CD3G, L __ lB. ATP2A3, NVL, RASGRP2, LCP1, CXCR4, PRKD2, GATA3, TRA@, .
KIAA0922, TARP, SEC31L2, PRKCQ, SH2D1A, CHRNA3, CD1A, LST1, LAIR?,
CACNA1G, TRB@, SEPT6, HA-1, DOCK2, CD3D, TRD@, T3JAM, FNBP1, CD6, AlF1,
FOLH1, CD1E, LY9, ADA, CDKL5, TRIM, EVL, DATFI, RGC32, PRK.CH, ARHGAP15,
NOTCH1,131N2, SEMA4G, DPEP2, CECR1, BCL11B, STAG3, GALNT6, UBASH3A,
PHEMX, FLJ13373, LEF1, IL21R, MGC17330, AKAP13, ZNF335, and GIMAPS, whose
expression indicates chemosensitivity to Methylprednisolone.
o) One or more of the gene sequences RPLP2, RPL4, HIVIGA1, RPL27, IMPDH2,
LAMRI,
PTIvIA, A1P5B, NPM1, NCL, RPS25, RPL9, TRAP?, RPL2I, L.AMR1, REA, HNRPA1,
LDBB, RPS2, NME1, PAICS, EEF1B2, RPS I5A, RPL19, RPL6, ATP5G2, SNRPF, SNRPG,
and RPS7, preferably gene sequences PRPF8, RPL18, RNPS1, RPL32, EEF1G, GOT2,
RPL13A, PTMA, RPS15, RPLP2, CSDA, KHDRBS1, SNRPA, IMPDH2, RPS19, NUP88,
ATP5D, PCBP2, ZNF593, HSU79274, PRIM1, PFDN5, OXA1L, H3F3A, ATIC, RPL13,
CIAPINI, FBL, RPS2, PCCB, RBMX, SHMT2, RPLPO, HNRPA1, STOML2, RPS9, SK.B1,
GLTSCR2, CCNB11P1, MRPS2, FL320859, and FLJ12270, and most preferably gene
sequences
PRPF8, RPLI 8, GOT2, RPL13A, RPS15, RPLP2, CSDA, KHDRBS1, SNRPA, IMPDH2,
RPS19, NUP88, ATP5D, PCBP2, 1NF593, HSU79274, PREVI1, PFDN5, OXA1L, H3F3A,
ATIC, CIAPIN1, RPS2, PCCB, SHMT2, RPLPO, HNRPA1, STOML2, SKB1, GLTSCR2,
45 .
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
CCNB1IP1, MRPS2, FLJ20859, and FLJ12270, whose expression indicates
chemosensitivity to
Methotrexate.
p) One or more of the gene sequences ACIB, C0L5A1, MT1E, CSDA, COL4A2,
MIVIP2,
COLIA I, TNFRSF1A, CFHLI, TGFBI, FSCN1, NNMT, PLAUR, CSPG2, NFIL3, C5orf1 3,
NCOR2, TLIBB4, MYLK, TUBA3, PLAU, COL4A2, COL6A2, COL6A3, JNTM2, PSMB9,
CSDA, and COL1A1, preferably gene sequences MSN, PFNI, liK.1, ACTR2, MCL1,
ZYX,
RAP1B, GNB2, EPAS1, PGAM1, CKAP4, DUSP1, MYL9, K.-ALPHA-1, LGALS1, CSDA,
AKR1B1, IFITM2, ITGA5, VIM, DPYSL3, JUNB, ITGA3; NFKBIA, LAMB1, FHL1, INSIG1,
TIMP1, GJAI, PSME2, PRG1, EXT1, DKFZP434J154, OPTN, M6PRBP1, MVP, VASP,
ARL7, NNMT, TAP I, COL1A1, BASP1, PLOD2, ATF3, PALM2-AKAP2, IL8, ANPEP,
LOXL2, TGFB I, IL4R, DGKA; STC2, SEC61G, NFIL3, RGS3, NK4, F2R, TPM2, PSMB9,
LOX, STC1, CSPG2, PTGER4, 1L6, SMAD3, PLAU, WNT5A, BDNF, TNFRSF1A, FLNC,
DKFZP564K0822, FLOTI, PTRF, BLA-B, COL6A2, MGC4083, TNFRSF10B, PLAGL1,
PNIvIA2, TFPI, LAT, GZMB, CYR61, PLAUR, FSCN1, ERP70, AFI Q, UBC, FGFRI, HIC,
BAX, COL4A2, COL6A1, IFITM3, MAP1B, FLJ46603, RAFTLIN, RRA.S, FTL, K1AA0877,
MT IE,. CDCIO, DOCK2, TRIM22, R1S1, BCAT1, PRFI, DBN1, MTI K, TMSB10, RAB31,
FLJ10350, Clorf24, NME7, TMEM22, TPK1, COL5A2, ELK3, CYLD, ADAMTS1, EHD2,
and AC __ f13, and most preferably gene sequences PFN1, HK1, MCLI, ZYX, RAP1B,
GNB2,
EPAS I , PGAM1, CKAP4, DUSP1, MYL9, K-ALPHA-1, LGALS1, CSDA, IFITM2, ITGA5,
DPYSL3, JUNB, NFKBIA, LAMB I, FHL1,INSIG1, TIMP1, GJA1, PSME2, PRG1, EXT1,
DKFZP434J154, MVP, VASP, ARL7, NNMT, TAP1, PLOD2, ATF3, PALM2-AKAP2, IL8,
LOXL2, LEAR, DGKA,.STC2, SEC61G, RGS3; F2R, TPM2, PSMB9, LOX, STC1, PTGER4,
116, SMAD3, WNT5A, BDNF, TNFRSF1A, FLNC, DKFZP564K0822, FLOT1, PTRF, HLA-B,
MGC4083, TNFRSF10B, PLAGLI , PNMA2, TFPI, LAT, GZMB, CYR61, PLAUR, FSCN1,
ERP70, AF I Q, HIC, COL6A1, IFITIVI3, MAP1B, FLJ46603, RAFTLIN, RRAS, FTL,
KIAA0877, MT1E, CDC10, DOCK2, TRIM22, RIS1, BCAT1, PRF I, DBN1, MT1K, TMSB I
0,
FLJ10350, Clorf24,NME7, TMEM22, TPKI, COL5A2, ELK3, CYLD, ADAMTS1, EHD2,
46
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
and ACTB, whose expression indicates chemosensitivity to Bleomycin_
q) One or more of the gene sequences NOS2A, MUC1, TFF3, GP1BB, IGLL1, BATF,
MYB, PTPRS, NEFL, ALP, CEL, DGKA, RUNX1, ACTR1A, and CLCNKA, preferably gene
sequences PTMA, SSRP1, NUDC, CTSC; AP1G2, PSME2, LBR, EFNB2, SERPINA1,
SSSCA1, EZH2, MYB, PRIM', H2AFX, HMGA1, HMMR, TK2, WHSC1, DIAPH1, LAMB3,
=
DPAGT1, UCK2, SERPINB1, MDN1, BRRN1, GOS2, RAC2, MGC21654, GTSEI, TACC3,
PLEK2, PLAC8, HNRPD, and PNAS-4, and most preferably gene sequences SSRP1,
NUDC,
CTSC, AP1G2, PSME2, LBR, EFNB2, SERPINA1, SSSCA1, EZH2, MYB, PRIM1, H2AFX,
HMGA1, HMMR, TK2, WHSC I, DIAPH1, LAMB3, DPAGT1, UCK2, SERPINB1, MDN1,
BRRN1, GOS2, RA C2, MGC21654, GTSE1, TACC3, PLEK2, PLAC8, HNRPD, and PNAS-4,
whose expression indicates chemosensitivity to Methyl-GAG.
= .
r) One or more of the gene sequences MSN, ITGA5, VIM, INFAIP3, CSPG2,
WNT5A,
FOXF2, L0C94105, IFI16, LRRN3, FGFR1, DOCK10, LEPRE1, COL5A2, and ADAMTS I,
and most preferably gene sequences ITGA5, TNFAIEP3, WNT5A, FOXF'2, L0C94105,
IFI16,
LRRN3, DOCK10, LEPRE1, COL5A2, and ADAMTS1, whose expression indicates
chemosensitivity to carboplatin.
s) One or more of the gene sequences RPL18, RPL10A, RNPS1, ANAPC5, EEF1B2,
RPL13A, RPS15, AKAP1, NDUFAB1, APRT, ZNF593, MRP63,1L6R, RPL13, SART3, RPS6,
UCK2, RPL3, RPL17, RPS2, PCCB, TOM.M20, SHMT2, RP. LPO, GTF3A, s-romu,
DKFZp564J157, MRPS2, ALG5, and CALML4, and most preferably gene sequences
RPL18,
RPL10A, ANAPC5, EEF1B2, RPL13A, RPS15, AKAP1, NDUFAB1, APRT, ZNF593, MRP63,
IL6R, SART3, UCK2, RPL17, RPS2, PCCB, TOMM20, SHMT2, RPLPO, GTF3A, STOML2,
DKFZp5643157, MRPS2, ALG5, and CALML4, whose expression indicates
chemosensitivity to
5-FU(5-Fluorouracil). =
47
. .=
=
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
t) One or more of the gene sequences ITK, KIFC1, VLDLR, RUNX1, PAFAH1B3,
H1FX,
RNF144, TMSNB, CRY1, MAZ, SLA, SRF, UMPS, CD3Z, PRKCQ, HNRPM, ZAP70, ADD1,
RFC5, TM4SF2, PFN2, BMI1, TUBGCP3, ATP6V1B2, RALY, PSMC5, CD1D, ADA, CD99,
CD2, CNP, ERG, MYL6, CD3E, CD1A, CD1B, STMN1, PSMC3, RPS4Y1, AKT1, TALI,
GNA15, UBE2A, TCF12, UBE2S, CCND3, PAX6, MDK, CAPG, RAG2, ACTN1, GSTM2,
SATB1, NASP, IGFBP2, CDH2, CRABP1, DBN1, CTNNA1, AKR1C1, CACNB3, FARSLA,
CASP2, CASP2, E2F4, LCP2, CASP6, MYI3, SFRS6, GLRB, NDN, CPSF1, GNAQ, TLTSC3,
= GNAQ, JARID2, OCRL, FHL1, EZH2, SMOX, SLC4A2, UFD1L, SEPW1, ZNF32,
HTATSF1,
SHD1, PTOV1, NXF1, FYB, TRIM28, BC008967, TRB@, TFRC, H1F0, CD3D, CD3G,
CENPB, ALDH2, ANXA1, H2AFX, CD1E, DDX5, ABL1, CCNA2, EN02, SNRPB, GATA3,
RR.M2, GLUL, TCF7, FGFR1, SOX4, MAL, NUCB2, SMA3, FAT, UNG, ARHGDLB, RUNX1,
MPHOSPH6, DCTN1, SH3GL3, VIM, PLEKHC1, CD47, POLR2F, RHOH, ADD1, and
ATP2A3, preferably gene sequences ITK, KIFC1, VLDLR, RUNX1, PAFAH1B3, H1FX,.
RNF144, TMSNB, CRY1, MAZ, SLA, SRF, UMPS, CD3Z, PRKCQ, HNRPM, ZAP70, ADD1,
RFC5, TM4SF2, PFN2, BMIl , TUBGCP3, ATP6V1B2, RALY, PSMC5, CD1D, ADA, CD99,
CD2, CNP,*ERG, MYL6, CD3E, CD1A, CD1B, STIVIN1, PSMC3, RPS4Y1, AKT1, TALI,
GNA15, UBE2A, TCF12, UBE2S, CCND3, PAX6, MDK, CAPG, RAG2, ACTN1, GSTM2,
SATB1, NASP, IGFBP2, CDH2, CRABP1, DBN1, CINNA1, AKR.1C1, CACNB3, FARSLA,
CASP2, CASP2, E2F4, LCP2, CASP6, MYB, SFRS6, GLRB, NDN, CPSF1, GNAQ, TUSC3,
GNAQ, JARID2, OCRL, FELL EZH2, SMOX, SLC4A2, LTFD1L, SEPW1, ZNF32, HTATSF1,
SHD1, PTOV1, NXF1õ FYB, TRIM28, BC008967, TRB , TFRC, H1F0, CD3D, CD3G,
CENPB, ALDH2, ANXA1, H2AFX, CD1E, DDX5, ABL1, CCNA2, ENO2, SNRPB, GATA3, =
R:R.1\42, GLU.L, TCF7, FOFRI, SOX4, MAL, NUCB2, SMA3, FAT, LTNG, AR_HGD1B,
RUNX1,
IVIPHOSPH6, DCTN1, SH3GL3, VIM, PLEKHC1, CD47, POLR2F, RHOH, ADD1, and
ATP2A3, and most preferably gene sequences KIFC1, VLDLR, RUNX1, PAFAH1B3,
HIFX,
RNF144, TMSNB, CRY1, MAZ, SLA, SRF, UMPS, CD3Z, PRKCQ, HNRPM, ZAP70, ADD1,
RFC5., TM4SF2, PFN2, BMI1, TUBGCP3, ATP6V1B2, CD1D, ADA, CD99, CD2, CNP, ERG,
CD3E, CD1A, PSMC3, RPS4Y1, AKT1, TALI, UBE2A, TCF12, UBE2S, CCND3, PAX6,
48
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
RAG2, GSTM2, SATB1, NASP, IGFBP2, CDH2, CRABP1, DBN1, AKR1C1, CACNB3,
CASP2, CASP2, LCP2, CASP6, MYB, SFRS6, GLRB, NDN, GNAQ, TUSC3, GNAQ,
. JARID2, OCRL, FHL1, EZH2, SMOX, SLC4A2, UFD1L, ZNF32, HTATSF1, SI-ID1,
PTOV1,
NNF1, FYB, TRIM28, BC008967, TRB@, H1F0, CD3D, CD3G, CENPB, ALDH2, ANX_Al,
H2AFX, CD1E, DDX5, CCNA2, EN02, SNRPB, GATA3, RRM2, GLUL, SOX4, MAL, UNG,
ARHGDIB, RUNX1, MPHOSPH6, DCTN1, SH3GL3, PLEKHC1, CD47, POLR2F, RHOH,
and ADD1, whose expression indicates chemosensitivity to MABTHERATm
(Rinndmab).
u) One or more of the gene sequences CCL21, ANXA2, SCARB2, MAD2L1BP, CAST,
PTS, NBL1, ANXA2, CD151, TRA_M2, IILA-A, CRIP2, UGCG, PRSS 11, MME, CBR1,
LGALS1, DUSP3, PFN2, MICA, FTH1, RHOC, ZAP128, PON2, COL5A2, CST3, MCAM,
IGFBP3, MMP2, GALIG, CTSD, ALDH3A1, CSRP1, S100A4, CALD1, CTGF, CAPG, HLA-
A, ACTN1, TAGLN, FSTL1, SCTR, BLVRA, COPEB, DLPA, SMARCD3, FN1, CTSL, CD63,
DUSP1, CKAP4, MVP, PEA15, S100A13, and ECE1, preferably gene sequences TRA1,
ACIN4, WARS, CALM1, CD63, CD81, FKBP1A, CALU, IQGAP I, CTSB, MGC8721,
STAT1, TACC1, TM4SF8, CD59, CKAP4, DUSP1, RCN1, MGC8902, LGALS1, BIILHB2,
RRBP1, PKM2, PRNP, PPP2C33, CNN3, ANXA2, IER3, JAK1 , MARCKS, LUM, FER1L3,
SLC20A1, EIF4G3, HEXE3, EXT1, TJP1, CTSL, SLC39A6, RIOK3, CRK, NNMT, COL1A1,
TRAM2, ADAM9, DNAJC7, PLSCR1, PRSS23, PLOD2, NPC1, TOB1, GFPT1, IL8, DYRK2,
PYGL, LOXL2, KIAA0355, UGDH, NFIL3, PURA, ULK2, CENTG2, NID2, CAP350, CXCL1,
BTN3A3, EL,6, WNT5A, FOXF2, LPHN2,.CDH11, P4HA1, GRP58,=ACTN1, CA_PN2,
MAP1L63B, GALIG,.IGSF4;IRS2, ATP2A2, OGT, TNFRSF10B, KIAA1128, TM4SF1,
RBPMS, RIPK2, CBLB, NR1D2, BTN3A2, SLC7A1 1, MPZL1, IGFBP3, SSA2, FN1, NQ01,
ASPH, ASAH1, MGLL, SERPINB6, HSPA5, ZFP36L1, COL4A2, C0L4A1, CD44,
SLC39A14, NLPA2, FKBP9, IL6ST, DKFZP564G2022, PPAP2B, MAP1B, MAPK1, MY01B,
CAST, RRAS2, QKI, LI-IFPL2., 38970, ARHE, KIAA1078, FTL, KIAA0877, PLCB1,
KIAA0802, KPNB1, RAB3GAP, SERPINB1, TIMM17A, SOD2, HLA-A, NOM02,
L0055831, PHLDA1, TMEM2, MLPH, FAD104, LRRC5, RAB7L1, FLJ35036, DOCK10,
49
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
=
LRP12, TXNDC5, CDC14B, BRMTILl, CORO1C, DNAJC10, TNP01, LONP, AMIG02,
DNAPTP6, and ADAMTS1, and most preferably gene sequences TRA1, ACTN4, CALM1,
CD63, FKBP1A, CALU, IQGAP1, MGC8721, STAT1, TACC1, TM4SF8, CD59, CKAP4,
DUSP1, RCN1, MGC8902, LGALS1, BHLBB2, RR13P1, PRNP, IER3, MARCKS, LUM,
FER1L3, SLC20A1, BEXB, EXT1, TJP1, CTSL, SLC39A6, RIOK3, CRK, NNMT, TRAM2,
ADAM9, DNAJC7, PLSCR1, PRSS23, PLOD2, NPC1, TOB1, GFPT1, IL8, PYGL, LOXL2,
KIAA0355, UGDH, PURA, ULIC2, CENTG2, NID2, CAP350, CXCL1, BTN3A3, 116,
WNT5A, FOXF2, LPHN2, CDH11, P4HAl, GRP58, DST', MAP1LC3B, GALIG, IGSF4,
IRS2, ATP2A2, OUT, TNFRSF10B, K1AA1128, TM4SF1, R13PMS, RIPK2, CBLB, NR1D2, =
SLC7A11, MPZL1, SSA2, NQ01, ASPH, ASAH1, MGLL, SERP1NB6, HSPA5, ZFP36L1,
COL4A1, CD44, SLC39A14, NIPA2, FKBP9, IL6ST, DKFZP564G2022, PPAP2B, MAP1B,
MAPK1, MY01B, CAST, RRAS2, QKI, LHFPL2, 38970, ARHE, K1AA1078, FTL, KIAA0877,
PLCB I, KIAA0802, RAB3GAP, SERPINB1, TIMM17A, SOD2, BLA-A, NOM02, L0055831,
PHLDA1, TMEM2, MLPH, FAD104, LRRC5, RAB7L1, FL335036, DOCK10, LRE'12,
TXNDC5, CDC14B, HRMTILl, CORO1C, DNAJC10, TNP01, LONP, AMIG02, DNAPTP6,
and ADAMTS1, whose expression indicates sensitivity to radiation therapy.
v) One or more of the gene sequences FAU, NOL5A, ANP32A, ARHGDIB, LBR,
FABP5,
ITM2A, SFRS5, IQGAP2, SLC7A6, SLA, 1L2RG, MFNG, GPSM3, P1M2, EVER1, LRMP,
ICAM2, RIMS3, FM1'L1, MYB, PTPN7, LCK, CXorf9, RHOH, ZNFN1A1, CENTB1, LCP2, =
DBT, CEP1, M6R, VAV1, JVIAP4K1, CD28, PTP4A3, CD3G, LIB, USP34, NVL, CD8B1,
SFRS6, LCP1, CXCR4, PSCDBP, SELPLG, CD3Z, PRKCQ, CD1A, GATA2, P2RX5, LAIR1,
C1orf38, SH2D1A., TRB@, SEPT6, HA-1, DOCK2, WBSCR20C, CD3D, RNASE6, SFRS7,
WBSCR20A; NUP210, CD6, EINRPA I , ALF1, CYFIP2, GLTSCR2, CI lorf2, ARHGAP15,
B1N2, SH3TC1, STAG3, TM6SF1, Cl5orf25, FLJ22457, PACAF', and MGC2744, whose
expression indicates sensitivity to an HDAC inhibitor. =
w) One or more of the gene sequences CD99, SNRPA, CUGBP2, STAT5A, SLA,
IL2RG,
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
GTSE1, MYB, PTPN7, CXorf9, RHOH, ZNFN1A1, CENTB1, LCP2, HIST1H4C, CCR7,
APOBEC3B, MCM7, LCP1, SELPLG, CD3Z, PRKCQ, GZMB, SCN3A, LA1R1, SH2D1A,
SEPT6, CG018, CD3D, Cl8orf10, PRF1, AIF1, MCM5, LPXN, C22orf1.8, ARHGAP15, and
LEF1, whose expression indicates sensitivity to 5-Aza-2'-deoxycytidine
(Decitabine).
Probes that may be employed on microarrays of the invention include
oligonucleotide
probes having sequences complementary to any of the biomarker gene sequences
described
above. Additionally, probes employed on microarrays of the invention may also
include proteins,
peptides, or antibodies that selectively bind any of the oligonucleotide probe
sequences or their
complementary sequences. Exemplary probes are listed in Tables 22-44, wherein
for each
treatment listed, the gene.biomarkers indicative of treatment sensitivity, the
correlation of
biomarker gene expression to growth inhibition, and the sequence of an
exemplary probe (Tables
22-44) to detect the biomarker genes' (Tables 1-21) expression are shown.
Identification of Biomarker Genes
The gene expression measurements of the NCI60 cancer cell lines were obtained
from the
National Cancer Institute and the Massachusetts Institute of Technology (MIT).
Each dataset was
normalized so that sample expression measured by different chips could be
compared. The
preferred method of normalization is the logit transformation, which is
performed for each gene y
on each chip:
logit(y) = log [(y-background) I (saturation - y)1
where background is calculated as the minimum intensity measured on the chip
minus 0.1% of
the signal intensity range: min-0.001*(max-min), and saturation is calculated
as the maximum
intensity measured on the chip plus 0.1% of the signal intensity range:
max+0.001*(max-min).
The resulting logit transformed data is then z-transformed to mean zero and
standard deviation 1.
Next, gene expression is correlated to cancer cell growth inhibition. Growth
inhibition
data (GI50) of the NCI60 cell lines in the presence of any one of thousands of
tested compounds
51
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
was obtained from the NCI. The correlation between the logit-
transformed.expression level of
each gene in each cell line and the logarithm of GI50 (the concentration of a
given compound
that results in a 50% inhibition of growth) can be calculated, e.g., using the
Pearson correlation
coefficient or the Spearman Rank-Order correlation coefficient. Instead of
using GI50s, any other
measure of patient sensitivity to a given compound may be correlated to the
patient's gene
expression. Since a plurality of measurements may be available for a single
gene, the most
accurate determination of correlation coefficient was found to be the median
of the correlation
coefficients calculated for all probes measuring expression of the same gene.
The median correlation coefficient of gene expression measured on a probe to
growth
inhibition or patient sensitivity is calculated for all genes, and genes that
have a median
correlation above 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 0.95, or 0.99 are
retained as biomarker genes.
Preferably, the correlation coefficient of biomarker genes will exceed 0.3.
This is repeated for all
the compounds to be tested. The result is a list of marker genes that
correlates to sensitivity for
each compound tested.
Predicting Patient Sensitivity or Resistance to Medical Treatment
For a given compound, the biomarker genes whose expression has been shown to
correlate to chemosensitivity can be used to classify a patient, e.g., a
cancer patient, as.sensitive
to a medical treatment, e.g., administration of a chemotherapeutic agent or
radiation. Using a
tumor sample or a blood sample (e.g., in case of leukemia or lymphoma) from a
patient,
expression of the biomarker genes in the cells of the patient in the presence
of the treatment agent
is determined (using, for example; an RNA extraction kit, a DNA naicroarray
and a DNA
microarray scanner). The gene expression measurements are then logit
transformed as described
above. The sum of the expression measurements of the marker genes is then
compared to the
median of the sums derived from a training set population of patients having
the same tumor. If
the sum of gene expression in the patient is closest to the median of the sums
of expression in the
surviving members of the training set, the patient is predicted to be
sensitive to the compound or
other medical treatment. If the sum of expression in the patient is closest to
the median of the
52
CA 02631236 2014-07-22
Stimg Of expression in the non-surviving members of the training set, the
patient is predicted to be
resistant to the compound.
Machine learning techniques such as Neural Networks, Support Vector Machines,
K
Nearest Neighbor, and Nearest Centroids may also be employed to develop models
that
discriminate patients sensitive to treatment from those resistant to treatment
using biomarker
gene expression as model variables which assign each patient a classification
as resistant or =
sensitive. Machine learning techniques used to classify patients using various
measurements are
described in U.S. Patent No. 5,822,715; U.S. Patent Application Publication
Nos. 2003/0073083,
2005/0227266, 2005/0208512, 2005/0123945, 2003/0129629, and 2002/0006613; and
in Vapnik
V N. Statistical Learning Theory, John Wiley & Sons, New York, 1998; Hastie et
al., 2001, The
Elements of Statistical Learning: Data Mining, Inference, and Prediction,
Springer, N.Y.;
Agresti, 1996, An Introduction to Categorical Data Analysis, John Wiley &
Sons, New York; V.
Tresp et al., "Neural Network Modeling of Physiological Processes", in Hanson
S. J. et al. (Eds.),
Computational Learning Theory and Natural Learning Systems 2, MIT Press, 1994
A more compact microarray may be designed using only the oligonucleotide
probes
having measurements yielding the median correlation coefficients with cancer
cell growth
inhibition. Thus, in this embodiment, only one probe needs to be used to
measure expression of
each gene.
Identifying a Subpopulation of Patients Sensitive to a Treatment for Cancer
The invention may also be used to identify a subpopulation of patients, e.g.,
cancer
patients, that are sensitive to a compound or other medical treatment
previously thought to be
ineffective for the treatment of cancer. To this end, biomarker genes, whose
expression
correlates to sensitivity to a compound or other treatment, may be identified
so that patients
sensitive to a compound or other treatment may be identified. To identify such
gene biomarkers,
gene expression within cell lines may be correlated to the growth of those
cell lines in the
presence of the same compound or other treatment. Preferably, genes whose
expression
53
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
correlates to cell growth with a correlation coefficient exceeding 0.3 may be
considered possible
biomarkers.
= Alternatively, genes may be identified as biomarkers according to their
ability to
discriminate patients known to be sensitive to a treatment from those known to
be resistant. The
significance of the differences in gene expression between the sensitive and
resistant patients
may be measured using, e.g., t-tests.. Alternatively, naive Bayesian
classifiers may be used to
identify gene biomarkers that discriminate sensitive and resistant patient
subpopulations given
. the gene expressions of the sensitive and resistant subpopulations within
a treated patient
population.
= The patient subpopulations considered may be further divided into
patients predicted to
survive without treatment, patients predicted to die without treatment, and
patients predicted to
have symptoms without treatment. The above methodology may be similarly
applied to any of
these further defined patient subpopulations to identify gene biomarkers able
to predict a
subject's sensitivity to compounds or other treatments for the treatment of
cancer.
Patients with elevated expression of biomarker genes correlated to sensitivity
to a
compound or other medical treatment would be predicted to be sensitive to that
compound or
other medical treatment.
The invention is particularly useful for recovering compounds or other
treatments that
failed in clinical trials by identifying sensitive patient subpopulations
using the gene expression
methodology disclosed herein to identify gene biomarkers that can be used to
predict clinical
outcome.
Kit, Apparatus, and Software for Clinical Use
This invention may also be used to predict patients who are resistant or
sensitive to a
particular treatment by using a kit that includes a kit for RNA extraction
from tumors (e.g., Trizol
from Invitrogen Inc), a kit for RNA amplification (e.g., MessageAmp from
Ambion Inc), a.
microarray for measuring gene expression (e.g., HG-11133A GeneChip from
Affymetrix Inc), a
rnicroarray hybridization station and scanner (e.g., GeneChip System 3000Dx
from Affymetrix
54
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
Inc), and software for analyzing the expression of marker genes as described
in herein (e.g.,
implemented in R from R-Project or S-Plus from Insightful Corp.).
Methodology of the In Vitro Cancer Growth Inhibition Screen
The human tumor cell lines of the cancer screening panel are grown in RPM"
1640
medium containing 5% fetal bovine serum and 2 mIVI L-glutamine. Cells are
inoculated into 96
well raicrotiter plates in 100 gL at plating densities ranging from 5,000 to
40,000 cells/well
depending on the doubling time of individual cell lines. After cell
inoculation, the microtiter
plates are incubated at 37 C, 5% CO2, 95% air and 100% relative humidity for
24 hours prior to
addition of experimental compounds_
After 24 hours, two plates of each cell line are fixed in situ with TCA, to
represent a
measurement of the cell population for each cell line at the time of compound
addition (Tz).
Experimental compounds are solubilized in dimethyl sulfoxide at 400-fold the
desired final
maximum test concentration and stored frozen prior to use. At the time of
compound addition, an
aliquot of frozen concentrate is thawed and diluted to twice the desired final
maximum test
concentration with complete medium containing 50 tierril Gentamicin.
Additional four, 10-fold
or IA log serial dilutions are made to provide a total of five compound
concentrations plus
control. Aliquots of 100 n.1 of these different compound dilutions are added
to the appropriate
rnicrotiter wells already containing 100 IA of medium, resulting in the
required fmal compound
concentrations_
Following compound addition, the plates are incubated for an additional 48 h
at 37 C, 5%
CO2, 95% air, and 100% relative humidity. For adherent cells, the assay is
terminated by the
addition of cold TCA. Cells are fixed in situ by the gentle addition of 50 ill
of cold 50% (w/v)
TCA (final concentration, 10% TCA) and incubated for 60 minutes at 4 C. The
supernatant is
discarded, and the plates are washed five times with tap water and air-dried.
Snlforhodamine B
(SRB) solution (100 111) at 0.4% (w/v) in 1% acetic acid is added to each
well, and plates are
incubated for 10 minutes at room temperature. After staining, unbound dye is
removed by
washing five times with 1% acetic acid and the plates are air-dried. Bound
stain is subsequently
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
solubilized with 10 mlvl trizrna base, and the absorbance is read on an
automated plate reader at a
wavelength of 515 rim. For suspension cells, the methodology is the same
except that the assay is
terminated by fixing settled cells at the bottom of the wells by gently adding
50 p1 of 80% TCA
(final concentration, 16 % TCA). Using the seven absorbance measurements [time
zero, (Tz),
control growth, (C), and test growth in the presence of compound at the five
concentration levels
(Ti)], the percentage growth is calculated at each of the compound
concentrations levels.
Percentage growth inhibition is calculated as:
[(Ti-Tz)/(C-Tz)] x 100 for concentrations for which Ti>/=Tz
." [(Ti-Tz)/Tz] x 100 for concentrations for which Ti<Tz
Three dose response parameters are calculated for each experimental agent.
Growth
inhibition of 50% (GI50) is calculated from [(Ti-Tz)/(C-Tz)] x 100 = 50, which
is the compound
concentration resulting in a 50% reduction in the net protein increase (as
measured by SRB
staining) in control cells during the compound incubation. The compound
concentration resulting
in total growth inhibition (TGI) is calculated from Ti = Tz. The LC50
(concentration of
compound resulting in a 50% reduction in the measured protein at the end of
the compound
treatment as compared to that at the beginning) indicating a net loss of cells
following treatment
is calculated from [(Ti-Tz)/Tz] x 100 = -50. Values are calculated for each of
these three
parameters if the level of activity is reached; however, if the effect is not
reached or is exceeded,
the value for that parameter is expressed as greater or less than the maximum
or minimum
concentration tested.
RNA Extraction and Gene Expression Measurement =
Cell/tissue samples are snap frozen in liquid nitrogen until processing. RNA
is-extracted
using e.g. Trizol Reagent from Invitrogen following manufacturers
instructions. RNA is
amplified using e.g. MessageAmp kit from Ambion following manufacturers
instructions.
Amplified RNA is quantified using e.g. HG-U133A GeneChip from Affymetrix Inc
and
compatible apparatus e.g. GCS3000Dx from Affymetrix, using manufacturers
instructions.
56
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
The resulting gene expression measurements are further processed as described
in this
document. The procedures described can be implemented using R software
available from R-
Project and supplemented with packages available from Bioconductor.
= For many drugs 10-30 biomarkers are sufficient to give an adequate
response, thus, given
the relatively small number of biomarkers required, procedures, such as
quantitative reverse
transcriptase polymerase chain reaction (qRT-PCR), may be performed to
measure, with greater
precision, the amount of biomarker genes expressed in a sample. This will
provide an alternative
to or a complement to microarrays so that a single companion test, perhaps
more quantitative
than rnicroarrays alone, employing biomarkers of the invention can be used to
predict sensitivity
to a new drug. qRT-PCR maybe performed alone or in combination with a
rnicroarray described
herein. Procedures for performing qRT-PCR are described in, e.g., U.S. Patent
No. 7,101,663
and U.S. Patent Application Nos. 2006/0177837 and 2006/0088856. The methods of
the
invention are readily applicable to newly discovered drugs as well as drugs
described herein.
The following examples are provided so that those of ordinary skill in the art
can see how
to use the methods and kits of the invention. The examples are not intended to
limit the scope of
what the inventor regards as their invention.
EXAMPLES
Example 1: Identification of gene biomarkers for chemosensitivity to common
chemotherapy drugs. =
DNA chip measurements of the 60 cancer cell lines of the NCI60 data set were
downloaded from the Broad Institute and logit normalized. Growth inhibition
data of thousands
of compounds against the same cell lines were downloaded from the National
Cancer Institute.
Compounds where the difference concentration to achieve 50% in growth
inhibition (GI50) was
less than I log were deemed uninformative and rejected. Each gene's expression
in each cell line
was correlated to its growth (-log(GI50)) in those cell lines in the presence
of a given compound.
The median Pearson correlation coefficient was used when multiple expression
measurements
were available for a given gene, and genes having a median correlation
coefficient greater than
57
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
=
0.3 were identified as biomarkers for a given compound.
=
Example 2: Prediction of treatment sensitivity for brain cancer patients.
DNA chip measurements of gene expression in tumors from 60 brain, cancer
patients were =
downloaded from the Broad Institute. All data files were logit normalized. For
each of the
common chemotherapy drugs Cisplatin, Vincristine, Adriamycine, Etoposide,
Aclarubicine,
Mitoxantrone and Azaguanine, the gene expression for the marker genes was
summed. The sum
was normalized by dividing by the standard deviation of all patients and
compared to the median
of the sums of patients who survived and the median of the sums of patients
who died:
NormalizedSum(compound) ¨
sum(marker genes for compound)/sd(sums of all patients)
Sensitivity(compound) =
[NormalizedSum(compound)-
median(Normaii7edSumdeadpatients(compound))]2
=
[NormalizedSum(compound) - median(NormalizedSumsurvivingpatients(compound))?
Figures 2 and 3 show the resulting treatment sensitivity predictions for two
of the 60
patients. All patients received Cisplatin and the prediction of survival
amongst the 60 patients
based on their Cisplatin chemoseiasitivity yielded the Kaplan-Meier survival
curve shown in
Figure 4. The expression of the 16 Cisplatin biomarker genes was first reduced
to 5 components
(dimensions) using Independent Component Analysis (fastICA). Five different
classification
methods were trained on the five components from the 60 patients: K Nearest
Neighbor with
K=1, K Nearest Neighbor with K-3, Nearest Centroid, Support Vector Machine,
and Neural
Network. Chemosensitivity or sensitivity to radiation treatment was predicted
by combining the
classifications of the five methods wherein each classification method was
assigned a single vote:
unanimous chemosensitive/treatment sensitive prediction resulted in a
prediction of
chemosensitive/treatment sensitive. All other predictions resulted in a
prediction of
58
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
chemoresistant/treatment resistant. The performance of the combined classifier
was validated
using leave-one-out cross validation and the survival of the two predicted
groups shown in
Figure 4. The survival rate of the patients predicted to be chemosensitive was
higher than the
patients predicted to be chemoresistant.
=
Example 3: Prediction of chemosensitivity for lymphoma (DLBCL) patients.
DNA chip measurements of gene expression in the tumors from 56 DLBCL (diffuse
large
B-cell lymphoma) patients were downloaded from the Broad institute. All data
files were logit
normalized. All patients received .Vincristine and Adriamycine and the
prediction of survival
amongst the 56 patients based on their Vincristine and Adriamycirte
chemosensitivity yielded the
Kaplan-Meier survival curve shown in Figure 5. The expression of the 33
Vincristine genes and
16 Adriarnycine genes was first reduced to 3 components (dimensions) using
Independent
Component Analysis (fastICA). Five different classification methods Were
trained on the
independent components from the 56 patients: K Nearest Neighbor with K=1, K
Nearest
Neighbor with K=3, Nearest Centroid, Support Vector Machine, and Neural
Network.
Chemo sensitivity was predicted by combining the classifications of the five
methods wherein
each classification method was assigned a single vote: unanimous
chemosensitive prediction
resulted in a prediction of chemosensitive. All other predictions resulted in
a prediction of
chemoresistant. The performance of the combined classifier was validated using
leave-one-out
cross validation and the survival of the two predicted groups is shown in
Figure 5. The survival
rate of the patients predicted to be chemosensitive was higher than the
patients predicted to be
chemoresistant.
Example 4: Prediction of chemosensitivity for lung cancer patients.
= DNA chip measurements of gene expression in the tumors from 86 lung
cancer
(adenocarcinorna) patients was downloaded from the University of Michigan, Ann
Arbor. Of the
86 patients, 19 had Stage ifi of the disease and received adjuvant
chemotherapy. Raw data was
logit normalized. Instead of the combined classifier described for the brain
cancer and lymphoma
59
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
examples above, the sum of biomarker gene expression was calculated for each
patient and used
to discriminate chemosensitive and chemoresistant patients. For each patient,
the gene expression
of the 16 marker genes for Cisplatin sensitivity (all Stage Di patients
received Cisplatin after
surgery) was summed. lithe sum was closer to the median of the sums of the
surviving patients,
the patient was predicted to be sensitive to Cisplatin. If the sum was closest
to the median of the
sums of the non-surviving patients, the patient was predicted to be resistant
to Cisplatin.. The
survival rates of the two predicted groups are shown in Figure 6. The survival
rate of the patients
predicted to be chemosensitive was higher than the patients predicted to be
chemoresistant.
Example 5: Prediction of Rituximab sensitivity for lymphoma (DLBCL) patients.
The method is not limited to cytotoxic chemicals. It is also applicable to
predicting the
efficacy of protein therapeutics, such as monoclonal antibodies, approved for
treating cancer. For
example, the monoclonal antibody MABTHERATm (Rituximab, RITUXANTm) was
examined.
Data for cytotoxicity of Rituximab in cell lines in vitro were obtained from
published reports
(Ghetie et al., Blood, 97(5):1392-1398, 2001). This cytotoxicity in each cell
line was correlated
to the expression of genes in these cell lines (downloaded from the NCBI Gene
Expression
Omnibus database using accession numbers GSE2350, GSE1880, GDS181). The
identified
marker genes were used to predict the sensitivity of DLBCL to Rituximab in a
small set of 14
patients treated with Rituximab and CHOP (R-CHOP) (downloaded from NCBI Gene
Expression Omnibus under accession number GSE4475). Conversion between
different chip
types was performed using matching tables available through Affymetrix.
= The survival of patients predicted to be sensitive to be R-CHOP is
compared to the
survival of patients predicted to be resistant to R-CHOP in Figure 7. The
survival rate of the
=
patients predicted to be chemosensitive was higher than the patients predicted
to be
chemoresistant.
To predict the sensitivity toward combination therapies, such as those used to
treat
Diffuse Large B-cell Lymphoma (DLBCL), patient sensitivity to a particular
combination therapy
is predicted by combining the marker genes for the individual compounds used
in the
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
combination. An example of this is shown in Figure 8, where the predicted
sensitivities of one
patient towards a number of combination therapies used against DLBCL
(identified by their
acronyms) are shown: R-CHOP contains Rituximab (MABTHERATm), Vincristine,
Doxorubicin =
(Adriamycin), Cyclophosphamide, and Prednisolone; R-ICE contains Rituximab,
Ifosfamide,
Carboplatin, and Etoposide; R-MIME contains Rituximab, Mitog-uazone,
Lfosfamide,
Methotrexate, and Etoposide; CHOEP contains Cyclophosphamide, Doxorubicin,
Etoposide,
Vincristine and Precinisone; DHAP contains Dexamethasone, Cytarabine (Ara C),
and Cisplatin;
ESHAF' contains Etoposide, .Methylprednisolone (Solumedrol), Cytarabine (Ara-
C) and
Cisplatin; and HOAP-Bleo contains Doxorubicin, Vincristine, Ara C, Prednisone,
and
Bleomycin.
=
Example 6: Prediction of radiosensitivity for brain tumor (medulloblastoma)
patients.
The method of identifying biomarkers can also be applied to other forms of
treatment
such as radiation therapy. For example, sensitivity to radiation therapy was
predicted for brain
tumor patients. Radiation therapy in the form of craniospinal irradiation
yielding 2,400-3,600
centiGray (cGy) with a tumor dose of 5,300-7,200 cGy was administered to the
brain tumor
patients using a medical device that emits beams of radiation. Sensitivity of
the 60 cancer cell
lines used in the NCI60 dataset to radiation treatment was obtained from
published reports. This
sensitivity was correlated to the expression of genes in the cell lines as
described above to
identify marker genes. DNA mieroarray measurements of gene expression in brain
tumors
obtained from patients subsequently treated with radiation therapy were
obtained from the Broad
Institute. The identified gene biomarkers were used to classify the patients
as sensitive or
resistant to radiation therapy. The survival of the patients in the two
predicted categories is
shown in Figure 9. The survival rate of the patients predicted to be sensitive
to radiation therapy
was higher than the patients predicted to be resistant to radiation therapy.
=
Example 7: Drug rescue.
Every member of a population may not be equally responsive to a particular
treatment.
61
CA 02631236 2008-05-26
WO 2007/072225
PCT/IB2006/004048
For example, new compounds often fail in late clinical trials because of lack
of efficacy in the
population tested. While such compounds may not be effective in the overall
population, there
may be subpopulations sensitive to those.failed compounds due to various
reasons, including
inherent differences in gene expression. The method as described herein canbe
used to rescue
failed compounds by identifying a patient subpopulation sensitive to a
compound using their
gene expression as an indicator. Subsequent. clinical trials restricted to a
sensitive patient
subpopulation may demonstrate efficacy of a previously failed compound within
that particular
patient. subpopulation, advancing the compound towards approval for use in
that subpopulation.
To this end, in vitro measurements of the inhibitory effects of a compound on
various
cancer cell samples from the responsive patient subpopulation collected
as.described above or
measures of clinical response of a treated patient are compared to the gene
expression of cells
from those patients. The growth of the cancer cell samples can be correlated
to gene expression
measurements as described above. This will identify marker genes that can be
used to predict
patient sensitivity to the failed compound. Preferably, biomarker genes will
be identified within
the patient population previously shown to be sensitive to the failed
compound. Once biomarkers
are identified, the expression of biomarker genes in patients can be measured
according to the
procedure detailed above. The patients are predicted to be responsive or non-
responsive to .. .
compound treatment according to their gene biomarker expression. Clinical
effect must then be
demonstrated in the group of patients that are predicted to be sensitive to
the failed compound.
The method may be further refined if patients responsive to the compoi Ind
treatment are
further subdivided into those predicted to survive without the compound and
those predicted to
die or suffer a relapse without the compound. Clinical efficacy in the
subpopulation that is
predicted to die or suffer relapse can be further demonstrated. Briefly, the
gene expression at the
time of diagnosis of patients who later die from their disease is compared to
gene expression at
the time of diagnosis of patients who are still alive after 5 years. Genes
differentially expressed
between the two groups are identified as prospective biomarkers and a model is
built using those
gene biomarkers to predict treatment efficacy.
Examples of compounds that have failed in clinical trials include Iressa
(Gefmitib,
= = 62
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
= AstraZeneca) in refractory, advanced non¨small-cell lung cancer (NSCLC),
Avastin
(Bevacizumab, Genentech) in first-line treatment for advanced pancreatic
cancer, Avastin
(Bevacizumab, Genentech) in relapsed metastatic breast cancer patients, and
Tarceva (Erlotinib,
Genentech) in metastatic non-small cell lung cancer (IsTSCLC). The method of
the invention may
be applied to these compounds, among others, so that sensitive patient
subpopulations responsive
to those compounds may be identified. =
Example 8: Median of the correlations versus correlation of the median.
The median of the correlations of the individual probe measurements to cancer
cell
growth as employed by the invention was compared to the correlation of the
median probe
measurements: this will determine at which step of the method amedian
calculation should be
performed. In the former, several correlations are calculated for each gene
since multiple probes
measure a given gene's expression, but only the median of the correlation
coefficients is finally
retained to identify biomarkers. In the latter, only one correlation is
calculated for each gene
because only the median gene expression measurement is considered for each
gene. Figure 10
shows the results of using the correlation of the median expression
measurements to identify
biomarker genes of radiation sensitivity predicting the survival of 60 brain
cancer patients. The
_difference in survival between the group predicted to be radiation sensitive
and the group
predicted to be radiation resistant in Figure 10 is much smaller than the
difference depicted in
Figure 9 which employed a median correlation coefficient suggesting that the
invention's median
of the correlations employed in Figure 9 outperforms the correlation of the
median depicted in
Figure 10.
If we look at individual marker genes like OMD, the median of the correlation
to
measured radiosensitivity Zif cell lines in vitro is 0.32.1he correlation of
the median, however, is
0.39. Adjusting the cutoff from 0.3 to 0.4 to compensate for the difference
does not improve on
= = = Figure 10, however.
We have also compared median correlation to weighted voting as proposed by
Staunton
et al., PNAS 98(19):10787-10792, (2001). Weighted voting produced a poor
result similar to that
63
=
CA 02631236 2014-07-22
of Figure 10, with a P-value of 0.11.
Other Embodiments
While the invention has been described in connection with specific embodiments
thereof,
it will be understood that it is capable of further modifications and this
application is intended to
cover any variations, uses, or adaptations of the invention following, in
general, the principles of
the invention and including such departures from the present disclosure that
come within known
or customary practice within the art to which the invention pertains and may
be applied to the
essential features hereinbefore set forth.
64
CA 02631236 2008-05-26
WO 2007/072225
PCT/IB2006/004048
Logenth =
List_3006: biomerkern identifitd in 2000 nninv thm new 1,1.334 e3-
14=m0014romeasto
latt 20051 biernirkern 1inthd in 2005 pAtcAt 1111h5
HU0400; biamarkers obtained With old gv6000 cbip mpa5ramOnt4
List Pri*ri VW4tehirm biola.tars in prior axt
List_pro6yxr: Pre4strxed3itt 06 hicm0=rkers
.CorrelOtIOnt eczeulation ot the biomarker to sensitivity to the compound
Table- 1. VinCriStine bi0M4Uers
Llat 2000 Liak_200 List Prior List Profs= 470,7,m-elat1on
11,1 MB UBS a.39
[2.] BPS4B RP54: 0.34
[341 810024 5100A4 0.32
010 unurs6 =UPS'S 0.31
U.S.J 52M .132X 0,35
t6,1 Cl4err139 C141:1139 0.3
0,7 MAN1A1 HAMA! 0.33
184 SLC25A5 SLO29115 SLC36A5 0,32
19,1 BP110 RPL1O 0,30
110,1 RPL12 RPL12 e.31
111,1 BTP5A =FBA 0,31
1124 2111.36A RPL363. BPS36A 0.3
113,1 41=1 Scx1 0-3S
(14,/ BLMS ST44B 0.32
(15,1 P1 =BPI. 0.32
(10,1 'MCA TBCA 0.3 -
/11,1 mpoz mom 0.34
ile,) DXS9419B 11X49829B 0.35
110,1 srRs3
12Ø1 ceal
(31,1 = RP139
122,1 usE25
123,1 BMA'
114,3 =CB
12541 RPLP2
120,1 RtL24
12744 RPS23
126.0 =1410
[29.1 11CL
130,1 BPL9
(31,/ pprAtiti
E32,1 RpS/0
[÷,1 Far3s2
[34,1 Sam.
135,1 RPS2O
136,1 _REA =
117,4 anion
0-8,1 HNRPAi -
(39.3 RPS41
[40,] MRS
141,1 Rf1.4
(47,1 4 = ftpr11-
1431.1 HReL12
144,1 Up7.102k
145,1 17
Table 2. Cisnlatia bioavoxlmrm
=
CA 02631236 2008-05-26
WO 2007/072225
PCT/1132006/004048
List 2006 It Z405 List_PriOr Last_Prafarr Corr*lution
(10 C1011.1 MORI 0.3
(2,1 EICLS1 OC1,51 OCLS1 9.33
(3,1 C853 C053 0.35
14.1 SLA STA 0.37
(5,1 1'ITA7 PTPA7 p2VM1 0.31
(5,) rwRox. PTVOCAF 11.32
(70 5RVITIA4 SNEW1A4 0.33
(3,) czwITA cuarral 047
pp) WIRAC rmitC 0.36
(10,) Trns zrzis Irt16 0-31
(11,1 Annul AREGRFO 0.35
[12,1 88C31L2 src31L2 0_32
=
[13,1 C1732 CD3O 0.32
(14,1 GAMS C3A8 8-3
(15,) C031) C23D 0.34
(16,) NAP411 MAPCO. 0.32
(17,) 411R65 CP345 0.39 '
(18,1 FRF1 PRP1 0.32
190 AREICAP15 1iR3GAP15 0.05
(20,) T16611 suusri 0.41
(21,1 TM% 1CF4 0.4
(22,1 OAPD
[23,] ARAODID
(24e) A0$27
125,1 C5orf13
125,1 LpErm
(27,1 =OFF
128r] 82M
(29,3 FTL
WA NCL
Intl NSU
02,1 KPO1
Table 3. Asuguaniaa biumarkars
List_2906 Mist_2005 List_Priar List Prafarr Correlation
/1,1 MN MsN RSN 0.34
(2,) SPARC crAmc am= 0.48
(3,1 YIN VIM vIN 0.47
[4,1 SRN SOM ORM 0.32
[5,1 14A331 scARB1 0.4
(6,) PIAT1 SIAM 0.31
(7,y C7cuP2 cu3P2 0,37
(8,] CA87 OAF) 0.34
(9,1 ICAN1 =Anil 0.43
(19.,] WASPUP WAZPIP 0.44
(11,1 ItM2A 22112A 0.31
(12,1 PALM2-0,NAP2 110112-Alth92 0.31
(13,1 ANPRP ANPOP 9.33
C14.3 PTPA61 PTPAS1 0.39
(15,) 8221 141#71. 0.32
(16,1 LAX LAX ' 0.43
)12,3 PC3R2A POGAZA. 0.3
[18,1 XMP3 EAP3 EX72 0.33
(19,) AVAx3 AuNA3 0,43
[20,] Evx2A 21/I2A 0.4
. [21,1 13783A3 81113A4 0.4
(22,) =1 LC32 0-34
(23,) BCAZ ACAV 045 '
(24.) 1T96 LT96 o.47
(25.) wpi LCP1 0.42
,
66
CA 02631236 2008-05-26
WO 2007/072225
PCT/132006/004048
(26,1 22=6 =16 0-33
(27.1 MCAM CCAM IMAM 0,37
(20.1 MEV28 MEP2C 0-41
[29.1 =IAA EIT,C1,11 0.49
[30.1 AT8= 112111A2 0.43
[3141 2721 PY0 0.31
[32,1 Pt VIAL 1741 0.33
(33.1 C10c238 CIarf30 0.37
(34.1 CMS. CHC1 0,33
135.1 CAPW3 cam o.s
(36,1 FO3R2C YCGR2C 0.34
(37.0 wax MIX 0.3$
[30.1 AMU/ AMPO2 0.3
[39,1 SEPTS SEPT6 0.41
[40,, RAFTlat RAPTLIN 0.3
[61A 0LC43.11,3 SLC4311.3 0.52
[42,1 RAc2 RAC2 0.33
(43.) LP211 LPICM 0-54
[44.1 CRIP-1 clar-L 0.33
[450 31.310539 PLI10539 0.33
[06,1 31.135035 FLJ35036 0.36
(170.1 DCCR10 000210 0.3
[45.1 13111/2 TRPIT2 0.31
[45.1 LERGZ0 1420 0.3
[50.1 Lrfl LE21 0.31
[51.) 0DAM151 ADAMTS1 = 0.30
E53.0 DDOST
[540
r$5,7 LGAI.91
(56,) CMW3
(57,/ SSRPB2
[WA EIF2s2
(590 RPRI1
(60,) YRSP1A
(41.1 CYPC
(42.1 IMOD
[03,1 MXRPAI
164.1 SND1
(05,) OOPA
(44.)
107,l 81Y3132
(62.1 Jorpts3
(OA DCMI
174,7 ammt
NAPS
02,1 POI/
113.) OR/SN-c1.56
(14,1 =rim
(75./ CUAI2
321.7
[77,1 PDPÃ39'
= (70,/ .14Y1
replan
L000 mr&
(01,) RAB7
OHS
TobU 4, tuova#Idc b4o.1,3,15cto
't2006 .it_Z0O5 List _prior List 2raf6rr corrlation
67
CA 02631236 2008-05-26
WO 2007/072225
PCT/IB2006/004048
(/,] C13509 0099 421309 0,3
12,1 25isml 32(32G1 0.3S
43,1 LAMM LAMS 0,32
14,1 aMMI . vital 0,34
150 num Hurt Lls
160 amst =Lai DOI
17,1 am 0:43 0,32
0,1 guk .:8" 13,37
po 55022 SSILV2 0,37
/10,1 GM GRE5 0.35
111õ1 myNa term 0.33
(I2,] MFG CMPO 0.32
[13,] 1232139 PU1109 0.31
[14,7 wrz2A Evm2a. 0.41
[100 PTP37 2.1,20/ 0.3
[100 PT03214 PSTMR4 0.3
(174 C.Itorf9 rxerf3 0.3
0.00 PTP2Ø4$45 PTPRC6P 0.3
(19,1 214714341 2.1[Fm1A1 0.35
[20,1 CUM gliNTB1 0.3
(21.1 PTEIC PTPRC 0.31
(22õ1 WAN= IMP= 0.31
(23,1 137..h..1312.h tta-bRA 0.34
(24.1 IPT16 xrx15 0.30
[25,1 00R01.4 0040111 0.3
=
(20,1 APAGEFfi AREGEr6 0.33
(i7e) PSC1113P PSCTST 0.4
(23,) SELPSM . 01:24FLG 0.35
(20,j LAT LAT 0,3
[30,1 Sme31L2 5=1=2 0.42
131,1 CMS C032 0.36
(32,1 SH2111A s1t.2131.4 0.33
[33,1 Gm4D GENE 0.34
[34,1 acsaA scim. c.'3
.
[35,] Itit ITK 0.35
[36,1 2a1.7LIN . RAPTLTU 0.30
(37,1 11007.2 rOCE2 0.33
C38,1 C5321 calb 0.31
[39,] 2.AC2 XAC2 0.34
(40,1 g30,70 ZAP:70 0.3$
(41,) OPE63 01%05 0.35
142,1 1.R4,1 pRri 0.32
[43,1 mae22715 44114GAP13 0.32
(44,1 Scucial NOTC141 0.31
(45,1 UBASU3A USASH311, 0.32
i4,$,1 WM
(47.1 NYC
[42,1 RPS24
(45,1 ppmr
(50.) P5EFL
ES1,3 AE325 .
Table 0. Adriamyain bitimPrkers
Ltst 2006 LiSt 2005 tist_PriOr L45t_Pxpf4Er Correlati40
[4,1 0.099 0050 c001 0.4/
12,1 LAPTMS LAP7115 0.30
[3,j A.1.00C AL00C 0.31
[4,] HCLSI. 147#31. 0.32 .
(5,1 C063 0003 0.31
(6,1 SEA =A 9.35
(7,1 002P2 OgPP2 9.34
_
,
68
CA 02 6312 3 6 2 0 0 8 - 05 - 2 6
WO 2007/072225
PCT/IB2006/004048
[0,1 1L23A IL2RC 0.30
[9,1 Gmra CHM 0.32
[10,1 Clfort9 CX*P.59 0.32
=
(11,1 A50138 tWOR 0.31
[12,1 9TPRCAP xmpacAF 0,42 .
(13.1 ZRTItlX1 IN241Ø1 0.43
[L4,1 CnUTS1 =mil 0.16
[15,1 TCt7 TCF7 0.22
[16,1 CO1C 0121.0 6.3
. (17,1 1AP4X1 RAP4XL 0.35
[18,1 00111 CD18 0.39
[19,3 0.030 cA3C 0.31
00,7 Melte PTFRC 0-19 .
[21,1 CCR9 C0R9 0.34
(22.1 c0X0IN COM= 0.38
(23.1 CXCP.t =CAA 0.3
[24,1 Alumair6 A380.13F6 0.31
[25,1 1011c1 n141. 0.32
[26,1 vas= 6M1,91,G 0.31.
[27,1 TaLT LAT 0.31
(28,1 sEC3LL2 SEC3EL2 0.33
[29,1 0035 CD33 0.37
(30,1 A1120/1.11 0112731A. 0.37
(31,1 C01A C01..A 0.4
[32,1 lalkl LATAL
[35,1 IL K TTE 0.3
[34,1 T1039 TAA9 0.34
135,1 1133D C030 0.33
[36,1 4BSC1t20C mA8CR200 0.34
[37,1 1AP70 1.A270 0.33
(38õ) 117144 T2X44 0.32
=
E30,1 orriAs 0PR65 0.31
[40,1 AT.21 AXFa 0.1
[41,1 ARRCA3I5 AARGA215 9.37
(42,1 NARP RARp 9.3
[41,] PACAP PACAP 0.32
1440 K12510220
[41,1 $1M
(40.1 T05,29,
[42.1 AARPI
[48õI R9627
[41,1 RARPA3
(53,1 c3X3
131.1 ARP3233
[52.1 OPX5
'
03,1 PPXA
(54,1 ORRA9
'
[550 unP,
T1 6. 0=1Attlb.1.0in Ibi4481*kore
List_2005 List _2005 Lint Prig= List Protetz cortiaatioa
(1,1 R9112 R9L11 0.3
[2,1 31PL32 RPL22 0.37
[3,1 R211,2 RPL02 5r192 0.37
14,1 NYS MYR RYA 0.52
[Sri 2189181,51 =maim. 0.34
15,1 8C11.91 6cA91 0.33
(7,1 STAT4 sTAT4 0.31
[8,1 81'140 3E140 0.4
E0,1 3rtne3 A01903 0.3
r10,1 I8mxr0 Itivaps 0.4 .
=
69
CA 02631236 2008-05-26
WO 2007/072225
PCT/IB2006/004048
ill4 TOK10 mX1V 0.31
(12,) TArs CRP'S 0.3
(13,4 VOL FEIL 0.41
E14,1 RPS2 AVS2 0.34
[15,1 PrPRC PTPRC 0.37
[160 mocaz .00CX2 0,32
(17,1 UPR05 OPR65 0.35
[20,) 5muit9 =AP 0.33
X1.712270 Fta12270 0.32 .
[20,1 BITRFD E03110) 0.4
[21.1 LARR1
(22,1 RPS26. =
=
[23,1 um
(240 WPM
[250 HURPL1
[24,1 RPSt
[27,/ ARP=
peo 1317413
129,7
t3Orf RPS1$11.
014
Tablai 7. Mitomentrond barbors
List 2006 List_2005 List Prior Lied. Preforr ccz.re10tion
(10 PGA141 Maul 0.32
(2.) DPYSL3 OPY3t3 0.36
[3,1 11MIG1 - 20201 0.32 _
[0.1 Gal 0.770. 0.31
[5.1 BETPI 00IP3 0.21
re/1 rA32 RAW, PRG1 0.39
[7,] GOPD G.¾BD 04150 0.34
p3,) BASP1 BASEL 0.32
Op] 1.1.002 P1.002 Q.34
(104 10=2 LIM/ 0.11
(114 1160P2 588P2
I127 CLor229 Clorf24 0.35
(13,1 VOX TaX 0.35
EL4,1 SVC1 STC1 0.39
11-9.1 mausint. =nem tornsna 0.34
114A Won 000 OIC0R2 0.3
(17.] 0411.1 WAP1L1 RAPLL1 0.32
116,1 2,009410% LOC94105 0.34
E10,7 C0162.2 catoa 0.3
120,1 AXACEP4 ARNCEF5 :mows 0.34
fZ,...] SAMAA GATA3 0.35
12201 TF72 ma 0.31
123,1 tat 1AT 0.31
1240 Cu3z CD$2 0.37
725,; AZ10 Ar10 0.13
[26.] MA.V1D HAP10 MAPIE 0.34
[27$1 22PBC PTPRC Ø31
[MI r31,3c4 . . PRXCA 0.35
[29,1 XR1.22 TR102 0.3
E30,4 COAD CD311. 0.31
[31,1 BCAT1 BCATI 0.32
=
[341 rF144 12144 0.33
(33.1 CCL2 ct3.2 0.37
[34,1 RAZ31 111.331 0.31
[]-5,1 CUTC CUT0 0.23
CA 02631236 2008-05-26
WO 2007/072225
PCT/IB2006/004048
(36õ) RAT1L2 2/11$1..L2 0.33
(37,1 6:1817 MKT 0.35
(38,) 21.321159 rsnalso 0.33
(39,1 C0L5h2 COL5A2 0.36
(40,1 62n
(41,1 05/3W-Ø..56
Ter2A
(430 21/121
(44,) Ptah
(45/1 1.141161
[46,) UltAPha
(47,) anis
=
=
(48,) . CSost13
(49r] Awns .
00,3 Too,3
(53...) HMG=
(524 1:113231
t-53,1 =5
(34,) PPM
(55,1 PSMS9
[56,1 =RP!
Table 2.. nitaawcift Dixemarker6
Li**. 2006 806600 1.41.04_yriot Li0t. lUtfrs' eacsclatios
[1,) STC1 STIC1 0.34
pi) MO nP1165 0.32
_
(3,1 DocK10 ppcx20 0.36
(41,1 C03512 OCT05A2 0.33
(5,] F7M416& PAN46A 0,36
(6,) /0054/03 L0054103 0.39
Table 9- Paclitaxal (Taxol) biamarkerm
LIst,...7006 H06600 List _Prior Liat Tiaferr Correlatiom
[1,1 RPL/0 RPL10 0.31 =
(2,1 0.1154X KT64x 0.31
13,3 OUDC NUM 0.3
14,1 KALY RALT 0.31
[5.1 D31 DKC1 0.3
ter] nra564cIa5 0X1o22504C136 0.32
[7,] 5DAP10 PRI7110
[8,] R5B0P60 RAIDOP410 0..13
[9,..] 33A9761 MEM9761 0.3/
[10,1 CnaS CMS 0.1
[11,] L.ar1 =PI 0.3
[12,] XL133.32 11,132A2 0.34
(13,3 kag13362 HAGHB2 0.41
1144 1017362 UMGM2 0.35
[154 .LM51 ALM51 0.3
[1.6,1 CPR45 GPR65 17.31
[17,1 1'L.710774 11.1]11774 0.31
(26,] KOLB KOLB 0.31 .
f16,) D7ZA01 Wan 0.32
(20,j SIC25A16 3w25405 0,31
[21,) P1P53 . 033'53 0.36
122,) Dxs1879K 0.1096712 0.31
(23.) PiTP8C1 VITP8C1 0.33
124,1 SPAN= ormxc 0.3
(26,1 KIAA1393 ni1A1391 0.33
71
CA 02631236 2008-05-26
WO 2007/072225
PCT3B2006/004048
201* 10. memcitabiuu (commo..0 bionarkers
last_2006 1406800 Llat Prior Liat Preferr Correlation
Ely] 19791 PPN1 0.77
(1,1 Peas/ PsAisl 0.35
(3;1 7c-AuPWA-1 k-3LPEA-1 0.34
[4,1 CM CSOA 0.31
(5.1 SCULL ecuAl 0,36
(6.1 PWP1 P71P1 0.37 17;1 PALU2-7K322 PALM2-AZAP2 0.31
(oil VOTSPIA turRarla 5,51
(9,1 AMPSG2 ATP5G2 0.36
(1.0,1 AP/0 AVIQ 0.31
EI1,1 VeM4 UNZ4 0.31
1/2,1 2200/ rumx1 0.32
Table It. TAT4i0ero (d000teXa11 'tie/Barkers
Lit _2D05 List 2005 mist _Prior idat_Prefetr ear.ttaatiatl
(4) ANIP32E A3P/25 0.45
12.1 071,34 CVM341, 0.31
(3.] Pits2 . Imm2 0.11
(4.1 TRIM14 MU:Mb 0.71
[SA 91tP2 S1P2 0.33
(6,] T327,13 MP/3 0,36
(7f] RP= RPC3 0.45
(2.1 CASP7 6A5P7 0.32
(941 12W fati 0.36
(10.] mAns5 NCNS 0.34
[11,1 P747552. PT0SS2 0.39
(12,] OSTC1 49PCI 0.37
(13,1 E13417,411 82214LL4B 0.32
(1441 chtma CALLA 0.31
Tab2e 12, oaxameteasome bialtarlmrs
1,16t_2006 S06900 7.i0t_Prien 7.ist Prefer: corr*Zattcm
(1,1 IrlTest IFIMIT2 0.38
U.) UHE2L6 U8732L6 0.32
(3.1 MAFTmS Lakr85 LAPTM5 0.36
(4,1 031.4 trap4 0.34.
(5,1 IT/1221 ITK2A 0.38
(6;1 17022 maa 0.42
. (70 A8023' AMP 0.11
(0.1 6053 605I 0.34
(9,1 T7.2710 U.2118 3.142RG 0.36
(1.0,1 6037 6037 0.34
[11,3 GPRAR91 GPRA,SPI 0.36
C12,2 PTY57 F1TN7 0.32
(13,1 cxort9 morn 0.16
(1-44) IT08 1.11013 mace 0.33
(15,) 421.2 C222 0.3/ .
(1.6.) AD0RA2A 3302.3.2k 0.31
(2.7,1 SNP/UM ZNPN1A1 0.35
(18.) 6NA15 C5315. 8I315 0.33
M.1 6591 . . 0E9,1 0.32
(20,) I597697 . Twe797 0.46
121,1g4P4g1 mA.V461 0.3
.
/22,1 00E7 COO 0.31
(23,3 6030 CD50 0.75
(24.) PTPAC rrnw 0.41
(25,) .470211.3 1VP233 A7P22.3 0.4
(26,1 VC92 13CP2 . 0.3
(27,1 Collotx amom cottotA 0.39
72.
CA 02631236 2008-05-26
WO 2007/072225 PCT/132006/004048
=
200 CATAZ =TAB CATA3 0.37
(29,1 CPER2.4 0022127µ 0.32
130,1 HEM REM 0.3
(31,3 TAM' TARP 0.3
[32,1 LAM. LAIR1 0.34
(33,) 6.11201A 4H2011 0.34
(34,1 =MX mix aLli 0.33
[35,1 3Z9T6 sEPT0 0.34
EA-1 112..1 0.34
137.1 cAP-437A CRE33L1 0031
[30,1 mAcc2 rpcc2 0.65
[39,/ c9310 00311 c0.310 0.32
[40,1 LsTl isT1 049
[41,1 AIF1 AlF1 0.35
[42,1 Ana Ana 0.$3
143,1 03TF1 DATF1 0.41
[44.; 3REC3P15 Amec3p15 0-3
[45,1 FAAZD MACS 0.31
[454 r'reol CRCR1 0.31
[470 Lcc01350 L9C01530 0433
[43.0 min2 EH= 0.37
Table 13. Ara-C (Cytarabiaa hyOroahlorida) biomatkewv
list._2006 EV6000 List...7dor Liat Prete= Correlation
[14) I1'323 I334.24 0.32
[2.1 REM 2moll 0-31
13,1 03XM1 p2.1P11 0.3
. [4,1 CEp1131 CENTB1 0.31
[$.,] GWE GmA15 0,37
[6,1 r0APEL1 Marlra Ratelta 0-31
(7,j A.Tp3G2 ATP5C2 0.31
10,3 300A3 CA333 0.33
15.,j 2AKCJ2 ykum.48 0.32
[104 522313 5E2D13 0.3
. [11,1 5E2T6 OMPT6 0.42
[12,1 PTE.= PTV= 0.33
[13õ1 2ME4 M3144 4.33
. 1144 K3L13 2P213 0.3
(1.5,1 C533 CD3D 0.11
(1.0,) COIE , COLS 4.32
[17,1 ADA Mk Am 0.14
.118,1 PROM PROD1 0.31 .
Table 14. Rethylyzedniapolone blamer-I:ars
L1st_2006 696000 List_Prior List...Prete= Carzslatiap
11,1 0D99 Cp99 CD09 0.31
[20 PRILM1 502341 0.31
(3,)MRCP= =EOM APEGDTE 0.31 .
[4,1 LAPTMS LAKUS 1.4.PW1.0 0.27 .
[5,1 VWF vvir 4.45
[0,3 120123 rsans 0.35
(7,1 32032 1'2022 I2G132 0.43
(BA LGALSP L13LS9 , LZAL50 0.43
19,1 IPP2-50 3330950 0_34
(10,1 !MEHL 2A231 . Isamu 0-32
(11,1 0853 0053 CD53 9.33
[12,1 T28r2 21.'022 Tr092 9.4
(13,1 DIA OLA nil 5.31
[14,1 IlaRG ilapp 1L2R4 0.3
115,1 67'6G ma. 0.3
. .
73 .
CA 02631236 2008-05-26
WO 2007/072225 PCT/IB2006/004048
(16,1 cn37 C017 0.37
(17,1 Gessk carm 0.4
(1801 a= smr.1 G.33
(29,1 C17092. C05152 con52 0.33
(20,1 LAMP Liimp 6.32
[21,j =AM icn62 0.38
mo A2111.3 Rim= 0.36
1230 PTP07 9,22127 rpm, 0.39
=
(24.) ARNOX125 1&nucam25 0.37
1350 1432 U:74 ACK 0.3
[260 Cgorr9 CZar/9 0.3
j27.1 AU= ANOIN REIM 0.5X
(26,1 PITAGAV VTrAcAP PIMCAP 0.5
(28,( czT2 62.02 0.33
[30,1 EDFOLA1 =mild, =MUM 0.5$
02,1 =Tin ccruni CE292111 0,38
(12,] 1.032 Lc02 t.34
[33,j 0711 sPi1 0.3
[14,1 GNAIS C[4215 . ONA15 0.30
[25,1 Onmn cmna 1.31
[36.1 CE21 cEN1 0.37
[370 BLIt mu 0.33
[31,1 CNN& 0002 0.30
(390 3chG1 SCAY1 0.32
(10,1 C62 CO2 0.40
[41,1 C6ic crac CDLC 0.37
342,1 1773597 monar7 0.31
[430 0A01 0AN01 0.41
[44,1 MA44N1 KAN4x1 0AP4XL 0.16
(45,] calt7 =0 0.17
'
[460 06cm112 c6=232 0.32
147,1 n1.OM1M3 AL02158 0.43
[440 BRIM 30-ur 0.33
(49,] CD= CMG CM30 0.51
000 1.1110 PTURC 0.37
[31,] LTa LTa 0.32
(52f1 A7V3 ATP223 1TNIA3 0,3
i51,1 NV]. MI. 0.31
154.1 WORM AN002P3 0.35
[95,) ACV1 2071 Le1.1 0.34
[560 c03.01A C0A01.3 CUIR21A 0.41
(67,1 CZER4 cmc04 CXCR4 0.3
[58,) P4Ra2 07RN1 0,33
ES0,1 3A6A3 on0A3 cAmA3 0.39
[6041 TRA0 Taal 0.4
[61,) PRXCal RaltC:62 ?Racal 0.35
[62,) mcml RMM1 0.32 =
[63,1 XtAA0922 IA.0922 0.36
144,1 TARP TAN.? 0.49
[650 300317.2 NAC311.2 0.32
j66.1 PRIM PAMQ 0.37
[67.1 SH21/2. 11/211A .. 0.33
1$8,1 C5RMA.1 CER7A3 0.5
(68,1 C016 VD12 0.44
170,1 L2T1 IST1 0.36
E71,3 LA/RI T.ATR1 0.47
(720 CACRALG CaCaala 0.32
(73r1 Mall TRa0 TRaf 0.31
(74,1 0EPT5 0E9%6 51820111 0.31
[79#1 HA-1 NA-1 0.42
. [76.1 DOCKZ 00CF2 0.32
'
. . -
74 =
CA 02631236 2008-05-26
WO 2007/072225
PCT3B2006/004048
07,1 Goo CD3D CO23D 0.41
(780 T200 MOP 0,39
EMI 23,711,4 T3a3m 0.37
(00,1 T3001 7u43P1 0.37
(01,) CDS CD6 n.4
($20 A.171 A171 Alla 0.31
MO 701#81 ma! 0.45
($4,1 COlt Colt CD1.3 0.00
Mc( LT% Lt9 0.39
(46,1 DOT3111/ wrzall 0.47
Le74 Am& AMA ADA 0.39
(54,1 47172.5 CD11.5 0.44
039.1 TRIM TAIX 0.3$
[904 NW. 3174 0.39
[91,3 OATP1 DATri 0.4;
[92,3 RRc32 AsC32 19.51
.
(93,3 9R7cH Plucca 0.1
(944 ARRGA015 ARBGAF15 0.34
[05,1 NOTCH]. pot= 0.38
195,1 141142 STR4 0.11
1914 Sma,44
Mid) OPEP2 DPE72 0.12
[99,] 4ECR1 CECR1 0.34
[100,1 $C.213 BcL1111 0.33
(101,1 09=3 . nsat3 0.41
(102,) 0AL015 GALNT5 0.34
[103,1 unast34 V0ASIE3A 0.3
(104,1 nut= ' PRE= 0.30
[105,1 27..313371.. ' tx..713173 0.34
11064 LEF1 2,771 9.49
1207,1 11.21R IL21R 0.42
(108,1 44=17230 mGc17330 0.33
1109,1 =APIA: . 1PAP13 0.5.3
(1104 Z1111-33.5 IsO7135 0.3
/111,1 GTHA75 Cztn79 0.34
Table 15. Methotrext.te biclsor34c3
Li.lt_2006 R06500 2.1*t_91ior Li.tt_Ptvfe.rr Corre14ti9m
(10 1..T9PO PRVF9 0,34
(2,1 PPL19 RPLI3 0.34
(3,1 RoVol ROP11 0.36
14,1 Dm= 8tD32 0.39
(5,3 GOPIG 7r771C 0.24
(60 40012 G012 0.41
(74 P03.I311 P91.1311 0.31
[Eta Mt nth MID. 0.41
(9,3 140015 RPS15 0.39
(10,1 WW2 911.02 Mtn 0.32
(11,1 CSDA. c&PA 0.30
[32,1 ROMS* OMMOSS1
(13.3 SORRA SORRA 0.31
(14,1 7142OH2 tru-.0a2 it0302 0.39
(15,) R9619 . 80519 0.47
(16,1 N0009 dupes 0.30
[17,1 A70.510 . ATTSO 0.13
[18,1 3C532 0051.2 0.32
(19,1 EN1693 389593 0.4
[20,] 119079274 80079274 0.32
i2/.õ) 08/81 rttml 0.3
=
CA 02631236 2008-05-26
WO 2007/072225
PCT/IB2006/004048
=
(22,1 1727736 P2mR5 = 0,33
123,3 axmIL (7271Am = 0.37
t24,1 m3F3m. 41732!.. 0.4.2
125,1 ATIC p.TIC 0.31
/26,3 R32.13 p21,13 0.36
/27,3 CUPL111 CIAPIN1 0.34
tzeo rig. rix = 0,33
[23,) RPM 3P62 RPS2' . 0.32
130,1 PCC6 PC2B 0.30
131,1 RIM ROMX 0.33
132,) .541145.2 001472 0_34
laao RFLPO RPLPO 0.35
[340 Meal EIMPPAI smRPAI 0.3$
/30,1 .61,01442 $20/11.2 0.32
/300 RP59 129,59 0.56
[37,1 EX/11 5903/ 0.23 =
/30,1 clam= GLTSCR2 0.37
(39.1 47C7401X1s1 CdMstxpl 0.3
(40,1 mpp02 mpps2 0.33
/41-3 r/.220350 210206521 0.34
[42,3 r2.312270 21,312273 0.2
TAhle 16. P1Abcol410 biemaxkers
1.ift_2006 006600 Liot_PrIzo 74.0t_prcfmwr 20rrsiatIcau
(1,1 SSW ffSW 0.3
[2,1 PFM1 PTA1 0.45
' PrI MI Axl 0.33
(4,] 2CTR2 ACTR2 0.31 (3,1 mcr..1 mcma 0.31
[6.-1 27X ISTX 0.22
E1 Rarlia Iiii12133 0.34
18,1 6ND2 cm0.2 0.32
13,1 EMU = 1,A51 0-31
(104 FMN&I Pram 0.42
.
111,1 CEP,P4 cf.hP4 0.31
(12,; 006P1 DUSPI 0.4
tI3,) KM, MXXS 0.4
(144 10-1112.21M-1 E-A1FF4-1 0.37
(xs,) ylnarl L3AL81 0.30
116..1 CSDA cSO4 CS. 0.3
117,1 AKR1B1 Aiat161 0.33
[10,) 22-2,2342 xpx2m2 3x22342 0.30
/19õ; =VAS XV105 0.43
f2Ø) VIM 1/141 0.39 '
= [21.1 ESPY6L3 1227s/.4 0.44
(-22.1 aums TUNA 0.32
C23,1 =Ma rT043 0.28
[240 HIMBIA 401,111,4 0.22
[25,] rAtaml LUTEL1 0,37
120,1.311/13 0711,1 9.31
MA 314S1G Fps's' 0.31 .
(20,7 TIPF1 wiaµel 0.48
09,1 Ca'Al QUI 0.54
(29,1 P0WM2 PPM= 0-34
(31,3 PROL PRG1 0..46
i32,1 MM. EX51 0.15
133,1 DX73114343154 ' pX771,434,7154 0.31
[34,1 arm OPT0 0.21
[3$,] M60R671 BMW' 0.52
. [36,1 MVP 191, 0.34
'
76
CA 02 63123 6 2 008-05-2 6
WO 2007/072225
PCT/IB2006/004048
(370) Amor VAlor 0.31
(30,1 ARL7 ARL7 0.38
[39,1 uumT MUM UMW 0.34
(40,) Tan . TArl 0.3
(4.1,1 c01.1A1 cOLL51 C0L1A1 0.33
02,1 Hama mASPI
t43,) Pm= PLOW 0.37
(440 Awn ATr3 0.4z
rob] TaLm2-Alcur2 PAL012-ARAr2 0,34
(46,) XL0 mo 0.34
1.47,1 AMBER A122E8 0.35
08,1 L04(12 Lox= b.22
Wrj Torn 2446101 0.41
00,1 EL44 12414 0.31
[51,1 DORA 0CRA 0.32
(52r1 owc2 5=2. 0.31
(52,1 82C610 SBE61.0 0.41
[5441 m3'2n3 urxr,3 10r/L3 0.47
t55,) 1cs3 kt53 0.37
[50r) =4 ra0,4 0.34
(57,t r.21c MR 0.34
(504 27242 TE112 0.3S
(59,) MMus' PSmE9 MOD 0.34
(50r) LOX 1.0-X 0.47
[Sir) STcl 0T01 0.35
(520) C0PO2 cST02 Co042 0.36
[63.) PT05B4 PTGER4 0.31
(640 114 IL6 0.34
530 SU= wan 0.30
60.1 Mau Pram LYIA0 0.35
(57,1 UNT5A timr15 0.44
60.1 HDRF =
snmr 0_34
(41,) TEPRW1A Turn0rLa IstrOSPIA 0.46
(70,] ?um RENE 0.34
171,1 ntru5645we22 Dmr554ma3z 0.44
(71,) 1'L0T1 rwra 0.30
(73,) prlip 00R2 0.69
174,1 BLR-2 81.4,-.8 0.36
L75,1 C0L60.2 ocaosma c02.443.4 0.32
(76,] M6C4003 N0C400$ 0.32
(77,1 INZA521.06 THFASF160 0.34
(700] IFLAOti ETA*T1 0.31
175,1 2)24h2 ramAt 0.30
100,1 22,81 TETI 0.38
161,1 LAT LAT 0.45
(Ea,/ GEM CEEB 0.51
[03,1 cxuAl CYRG1 0.37
(84,) 2150u PLR. MAUR 0.35
(05,1 PS= PSEN1 roCM1 0.32
(04,) ER270 ER270 0.32
(07,1 APIQ Arlij 0.3
tes,) UBE COE 0.37
(0,, rar21 F8FR1 0.33 '
(00,) arc 112C- 0.33
tol , j Ilar em 0.35
to2rj coL4z2 EOL482 C0L4A2 0.32
to3,) C0L0A1 C0L5A1 0.32
(44,1 I2/283 xrx-wm) (,
195,1 1(A1'la MA1'113 0.34
(MI 21446603 2r446603 0.37
. 197,J RAFTLIR RAr73..XD1 0.34
. .
. 77
CA 02631236 2008-05-26
PCT/1B2006/004048WO 2007/072225
[MI RRAS - ARAB 0.31
r90.,1 VtL v.= 0.3
/1410,1 xxa1%.o077 XIARO$77 0.31
/2010 )4210 grtg gp110 0.31 .
/102.) =10 cw30
1/630 3OC22 ' 0CFC22 o.32-
(104,1 T1I122 mg=2422 000
(1050 gig/ RX5i 0.37
(1104.1 3CA21 . CCAT1 . 0.42
(107,1 3g121 P RP 1 0.34
iloso DIM 01301 0.36
(105.01 Wag MX 9.3
(A/0,1 MARIO 500010 0.43.
(111..] 310.701 nAn3i. 0.4$ .
11124 'LS103.50 PL.710350 0.,4
11/3,1 clor/20 ctori24 9,34
(114,1 siggl mmal 0.4$
(I/5õ) Thr.m.22 TgEm22 0.3
11/0,1 TP74 TFIC1 0.37
(117,1 cm5a2 . c0m--5.10 9.34
(110,1 ExH4 HT.,R1 0,30
I1 =a Cran 0,4
ii20,1 ROART51 6.D6,RTS1 . 0,31
(121,1 g(032 2002 0.41
1122,1 ACTD ACTD A.C2B 0.33
=
Table 17. gothyl-GAG (Methyl girl:gat bi0(aMitti001:01c900r*,
dilYeiroth,14,110-
1..ist_2008 536000 Litt Prior Liot Pregorr Porrtiatio9 .
(1.,) puts, MIX 0.33
(24) 55RP1 = =rex 0.37
(3,] RUDC HUDC 0.35
(4,) CM5C C2sC 0.35
15,0 REIG2 AFI.C2 0,33
O.) PmgE2 p074102 0.3
04 Mg . Lag 0.39
(3,1 311032 100,103.2 0.31
tDay marmi 0 0E33.130.1 0.34
(10.1' 400CA1 = s53031 0.32
[11.1 Z4V2 105112 0.30
(120 Kra gsg MYR 0.14
E4-7-,1 VAIMA 3.0110t 0.39
[14,1 32AFX m2AFX 0.13
[13,1 04a41 gmaml 0.35
(10,1 MOIR ummg 0.33
C17.1 722 222 0.42
ILIA U41SC1 Ws5C1 0,1$
11.9.] 813.5II1 0E1Pg/ 0.14
(20,) L304.13 LAMM 0.31
MO 83.3.611 DPArdr1 0.4.2
(22,1 UCK2 =K2 0.31
(23.) 0022=1 3.E3.21301 0.31
(24.) MINI gml 0.55
425,1 333741 gmggl 0.33 '
100,1 90102 43052 0-43
(270 3.E.C2 RA= 0..35
(20,) M8C21.554 0001021654 0.36
(254 3TSE1 1010e1 0.35
(304 TA1063 . 104=3 0.31
4.310 20.3E2 . 31.E32 0.32 =
=
=
. .
,
78
CA 02631236 2008-05-26
WO 2007/072225
PCT/IB2006/004048
tn.') 'ca PIACS 0.31
[334 RORPO NORM) ' 0.35
(34o] PN8S-4 ' P1AS-4 0-3
'
-Table 16, garb...10_3as Momarkers
List 2096 806906 Liskyr4?= Last Proelwr Corpolgt100
(IA MgH NCR 0.31
12,3 =CAS rTGA5 0.43
(3,1 VIM UM 0.34
(4,3 TO2AL2.3 TWAS1'3 0.4
54 C.92,02 cur=
16,1 164/ZA WHVgg 0.34
(7,] roXr2 ruicr2 0.36
f8,] LOC9,2105 LOGR4108 0.32
[9,] 21-216 MF11.6 0.38
(10,1 Lrmil LH8243 0.33
(11,1 =HAI 1039311 0.37
(12,] nuC810 D0CKI0 0.4
(13,1 =min LEM' 0.32
(I4,j coLsai COL5A2
(i5,1 AD2.UTS1 140AN2SL 0.34.
2a1,141, 2. 5-17g (5.-r16,0g441=1/4 14.4marIvIrm
Limt_;006 K01400 Limt Prior Li.vt Prete= Correlation
[101 RPI,I8 HP2,10 0.19
[2,3 021,10A rox,10/4 0.36
[34 luirs1 Rurs1 0.3
(4,3 glogre5 ANArg5 0.5
(5,1 Jase182 221,t1g2 0.4
(6õ) Hr1.13A 1111,13A 0.30
(7,1 Hr315 11'515 0.34
[L..] AMP' grAPI 0.27
(9.0 prourAul =MAIM 0.3
410,1 grAT APIU 0.32
(11,1 Egr593 324r533 0-37
(12,3 MRP53 mm63 0.31
1134 11.0 r1,60 0.31
(144 grL,13 2pLI3 0,31
(154 38gm2 S2323 0.35
(104 1vs0 HESS 6.49
(17,1 0=2 02112 0.38
(184 RP= RPM 0.32
t194 2P2.17 0PL17 0.34
[204 gPs2 gPs2 0.32
[21.4 POCH PCA78 0.31
122,1 TOMM26 = To2cm20 0.30
,
(23,1 88022 STOM2 0.36
(2'4,1 1172.P0 'LPO 0.3
Mel GTF30, C1T31. 0.5
126,1 820)41,2 S1'0141,2 0.4
(27,1 usrs12564.7157 Ogr415643157 0.30
(280 rairs2 mroz 0.34
(29,) AL,G ALM 0.37
(30,) CRUM abstm4 0.3
=
=
. .
79
-
=
08 .
64.0 rmao zoon P05]
OP'D ratA61 raeanz Iltgl
C'0 demo deva t'653
Oe'0 TIMM/ /g%Vg ['CS]
t..0 ENERV tH/eD Pcs]
LE-0 Tts.taV EUX3V i'Tgl
6E-0 ruird row l'Ogl
Se'0 Odv0 Ddva f'60
xam
se'd /XVd 97Ea4 ['LS')
et'o Com= ed.O.a ['04,1
Z540 SC2On sEsEn Psyl
sc-o ra..14 =amt. ['PP)
g40 VZO00 'tams E'tvl
Le-0 crEND 5/1610 F4xpl
tr. TIWG ITG.
['It]
RE-0 TLxv /jair 140V]
9C'0 tx.psau rAdlax [46t]
et-0 EDWe'd CPPICa 1,00
rt-0 /gimp /mug
Gp-0 Mao alea [40E]
OP'9. YE= villa [4CE]
9C-0 SEW 7E45 [400
'WO WIEN 44rEW t.re]
Lt'll 042 Wi.3 t'rei
8P'0 gua 441:0 l'IE1
eP'0 ran LE:D ttocl
ee'0 60a0 6040 (6J
te'd WV IftlY [ tar]
zt'O atm atop t'LC1
'co =lima Somma l's0
te'0 =VII xava
Pisti
Zr0 rotAoasx rizt#9,741r 1'90
te"0 tdZOSA4 raltramaa tiCtl
Tc`o tXkg illig PrCI
C*0 told zoiaa lizzi
EC*0 SIC0NZ reasEdim [40E1
SE'0 Sale
SO.EN 1,611
TC*0 Teat!' ladt Pet)
sr-o CLAW Laos t'Lll
st,-o CIABAM MINH 19E1
TE-0 0.12HE Coma esti
= tc-o s tap
SEQD l'Ittl
IP-1 WIC 94101 i'ttl
LC"0 elES axs tict1
SE=0 vls V7g VIII
et-0 sex 210./ Voti
LC*0 I SIM TRAP V63
.
1440 ggstit EuleriZ Pal '
at=O %Ism! 0.0tam 1,41
Ct.'0 xatR xata I'1
LC40 egIFIVAVd ttrommva l's]
= EC-0 IX= CXNett
VIA
6V0 ulau uld/A l'ELI
9E-0 End= 1312.1 11E1
OC'0 HMI IIT Vti
007-4rIeurx00 ix038-74-40TE zoT-Ed-40T7 900C-LIAT7
0mmeMmX74 (7,40114qu14) gruglzmtira *OZ *Ign
8t0t00/900ZEOLL3d SZZZLO/LOOZ OM
9Z -5'0 -800 9ETE90 v3
=
18
_
WO ORtt sun I'LtI)
WO toVol 1:42 I'M)
tr*0 . cvos tvW8 PM)
Ern tams zvOss i'1,111
E "0 wait' mill 'MI
E*0 yxos 1,X0s "ZI/3
tE-0 masa playa 6E*0 61330 Lau, Jell)
red Icem gnu -Ns.o.11
Wo mom max "eall
WO CvSVO Eva= 'Lot)
we tAsus saws 'yin)
SCO EORU Zona i$OI1
Co moo rialto 't011
CO 'MY tatV 'CHI
WO SIMI SXCe 'MO
Et. 2/170 2r= 'Tat)
ts-a %Arm Rawl! '00tY
' sup *Mot TVitot "66)
ECO ZHOW = =Iv 'se)
WO 1141220 Ham 'LSI
1,-0 IDIVO suap '96)
WO a eao Mao "s81
98*0 axes SAW "tpsi
te-0 mull oval, 'ES1
CO asum Balla 'Z6
9-0 Lases:mos nastmos 've
WO SZMtum MR= '08
L17-0 ELLE GU '68
Or'0 WICK taXS '88
ZP*0 tAo/A tA014 'Le
0,0 taus 14118 '98
St'a LasiTUU 1464VLS "Se
se- a MANZ ZE411Z "Ye
Te's 186IRS I.16.1203 4C14
re ataan alma 'ze
se-a zvtOaS Mom. 't8
SCO XORS Ems 'Oa
a-0 = ZEZH ZEIZt 'St
9S'0 Tam taMA Pet
S'D "IltDO 'MOD ['U. .
WO =alto =Syr t'9/.
t,S'D OVuer *vas
ti 0 tOsal, tOsaL i'VL
91,0 Ovalo *MO i'CL
CC0 'Ludo tzsdo 1"EL
be-0 WIR San l'tL
YCO ova* s470 1'04
1,4*0 9VS4S 98744S 1'69
Ca aXsi inat PUO
VE'0 Sdgit 9deTa. I''49
SI'D zaaa zaom (198
SE*0 tariC *aZa ("S9
TE*0 gawp ZdSUD (41*
WO UM usira tACO
gt, a vas-al ,t7SZRZ ("ZO
.4.C*8 maw= Vanovo l't9
zE40 *roma totaxv t'00
VS*0 MU= Vitiallso P6S
WO testo 'MEd rips
9E-0 Ream LIMO 1 'Ls
8t0t00/900ZEWIDd SZZZLO/LOOZ
OM
9Z-50-800Z 9EZTE9a) VD
CA 0 2 63 1 2 3 6 2 0 0 8-0 5 -2 6
WO 2007/072225 PCT/IB2006/004048
i
[118,1 1s3fl1x8 AmICI3X15 0.38
(1J.8,1 107/412 Drux1 0.38
(1200 memosp86 W80S8116 0.5
(121,) ocTs1 Dcmul 0.34
(122,y sa34xL3 811312L3 0.30
t123,7 vxm vxm 0.41.
(1244 pLmrsci PLEXACI D.3
(125,y cm47 ' C047 0.32
[125,I P01828 P01312F 0.37
[1274 miCal ATIOn 0.41 '
i1Z74.1 Appl AD81 0.48
(1.29,1 ATP2A3 ATP2A3 D.39
. .
=
Tabae 21. Radiation aansitivity biamarkore
L4.nt...2000 006000 List Prior List Praferr Corte2.ati40
11,) TWA TAA1 y.36
(241 Acms4 ACT84 0.36
(3,1 WADS MARS 0.39
14,1 c0r441 CALM1 0.32
(8,1 cm63 CD63 C863 0.32
t6,1 cool =81 0.43
t74 molplik EKBP1A 0.38
ted CALM CALM 0.47
.190 TOGIAP1 xmakipl 0.37 .
110./ CTSB cmsa 0,31 III.T MGC0721 M008721 0.35
(120 STA= STB31 0.33
(130 TACC1 TACC1 0.41
14,) TE40E0 xn4sr0 0.33
(150 nn59 0559 0.31
116,) CKA24 camP4 cuaRA 0.43
t17,) DusP1 DUSP1 BUSF1 0.30 .
[18,1 RCM. 82181 0.31
=
(15,) mcc8902 M008902 0.25
[20,1 1,BAL51 LCALS1 T1rs1 0.33
(21.7 9HLS152 t8.21322 0.3
y22,1 Min. REIBP1 0.31
(23,) 0Y.M2 PKM2 0.33
(14.1 PART' F11117 0.42 .
(25,7 R88228 FFF2CB 0.31
(26,) cmil CHN3 0.36
[27,] AUX42 AUDA2 sms.A2 0.32
[28,] 1E= XER3 0-34
[29,1 .7Alci XAK1 0-33
00,1 mamma MARCKS 0.43
C31,/ Lum LUK 0.48
[32,1 82(211.3 .5138.1L3 0.47
(31,) 5L020A1 s1.c20A1 0.41
[34.) 2284.03 zrr4Q o.36
(35,3 NEXS 11233 0.46
186,) EXT1 ExT1 0.47
(37,) 231.1 5'.78.1 0,32
[30,1 2281. cTSL C-B.51, _ 0.10
(3,1 SLC3916 51239A6 0.36
[400 8.10s3 taco* 0,38
141,1 CRE CRK 0.33
[42,/ NIAMT M1DIT 0.33
(43,1 coE1n1 OOLLAI #.3$
(44,3 110.42 TRA22 TRA142 D.35
[45,1 DRAM, ).3AB3 0.02
[46,1 DRAJC7 2NA4C7 . 0.38
=
=
=
. 82
=
CA 02631236 2008-05-26
WO 2007/072225
PCT3B2006/004048
=
[470 C2.1 1.1,9491 0.35
(49,4 PRSs23 PR.04123 0,3 .
(49,1 =az FLOM 0.36
150,1 N7c1 19PC1 0.39
151,1 TC01 TC011 0.37
1520 WW1 GPM. 0.47
153,1 ILO no 0.36
1540 DYRR2 Dnuic1 0.3
05,1 p2GL 2101. 0.46
(56,] sossL2 =ma 0.49
070 zamA9355 XXAA0355 0.26
(0,0,] um= DODO 0.49
09,1 116113 NFELS 0.53
1690 8066 MA 0.32
161,1 ULK2 . UMR2 0.37
(62,1 C3NT112 CENT= 0.35
(63,1 HIM M1n7 0.42
(64,1 CAP" cAR330 0,31
(63,1 c9c2.4 excla 0.36
[660 USI43441 BRE38.3 9.35
WO 246 71.6 0-32
166,1 wITV5A uNTSA 0-3
169,1 30Xr2 Po= 0-44
170,1 2.09x2 s3'5N2 0_34
[71.1 03911 cs6111 0,34
1720 P4RA1 P41161 0.33
(730 RP58 018p58 0.44
(74,1 ACTni ACT011 ACTN1 0.41
(75,) CAPD2 C3P12 0.34
[760 DEMI OSIII 0.44
[77,1 MAPILc3.9 NAD1LC39- 0.3
(76,) 0AL20 GAL= car= 0.36
(790 165r4 I2s3'4
(00,1 iR52 I1132 2,30
191,1 A.7.42Aa ATP2A2 0.35
(02,j 002 CGT 0.3
(23,1 1,87281,102 2erliSr105 0.31
04,1 Em2,611-26 1EAR1128 0,35
[85,1 2144spi 2/44521 0.35
1060 R62043 ROOMS 0.41
(07,1 nip= 01932 0.42
105,3 CS= Ma 0,46
(29,1 NR112 N0302 0.47
00,1 UTN3A2 OTN3X2 0.36
(91,] 31.C7All =7811 0.4
02,1 m031.1
030 3ar3V3 r07223 molava 0,31
194.1 0632 ssA2 0.36
05.1 FRI. rul 2.611 0_32
(96,) 0.001 3Q01 0.4
[520 ASPR ;OPEC 0.36
[se,] .66833 3.S8R1 0.33
000 MGM MGM. 0.35
/100,1 3E827536 = ssRpIND6 0.91. =
[103,] RSPAS 06935 0.33
(102,1 529363.3 372.361.1 0.39
(103,1 001.4162 c0L40.2 0.3
(104,1 411.491 C0L46.1 0.1
1105,1 c15,44 C044 0.35
1106,1 53c19A16 SLC34A14 0.30
11a7,1 816.62 6123-2 0.36
83
CA 02631236 2008-05-26
WO 2007/072225
PCT/IB2006/004048
[108,1 Fr8F9 11091.9 0.48
[105,1 11.65T 11,08T 0.4
[110,1 =n1,$6462022 ncF1F56442022 0-39
(111,1 PPAP211 minpzB 0.33
(112,) KAPI.a. KAP/2 0.3
(117,) KA0X1 mum. 0.3
[3.14,] MX018 mon 0.38
(115,1 casr CAS'S chse 0.31
[116,1 lums2 IMA82 0.52
(117,1 amz 00a 0.31
Eile,) Ler11.2 1.08,1.2 0.36
(119,1 8CFT10 SZPT10 0.10
[120,) ARUM ARUZ 0.5
0210 E/24,1070 lit2.A1079 0.34
[122,1 ns FTL 0.30
(123,1 KZ2A0877 x2.844877 0.81
11240 mcs1 3'X.c31 0.3
(125,1 WTA11.0802 )xAA0802 0.32
[126,1 NIVOI liti4M1 0.37
[127,1 8.4830AP Hats3C24A. 0.43
(1.29,) 8111011481 0ERFIN01 0.46
1125,1 TXMMI7A T2EI1I7A 6.38
[X30,1 S002 8002 0.39
(131,] 5n2.-A 111A-A 11ZO.-A 9.33
[132,1 80E932 40m02 9-43
[133,1 L0c35831 1=55021 9.32
[134,1 3ELDA2 PIILDPA. 9.32
[135,1 7Arl" 2ME42 4,47
[136,1 ktiql SLF8 9.35
[137,1 rAD104 F313104 0.34
[130,1 LARC5 MRCS 0.42
[1390 2AB7L1 1AF.71.1 0.41
[140,1 FL.735036 r1.33$036 0.36
[141,1 D0CK141 00=10 0.41
[142,1 1.1t1.12 LRF11 0.36
0.43,1 TIOIPc6 mmutc5 0.4
-
[144,1 CDC148 C0C143 0.39
1145,1 0RUT/L1 sa42,12,1 0.38
(146,1 CORDIC C01031C 0.38
f347,] 09.0=20 042510 0.11
E1-4174] T8v431 T01,01 0.31
[149,1 LOW. T.014P ' 0.32
(150,) 351002 AMIG02 0.23
191.] mainTis D29W4 0.31-
[12,7 ADAX381 AnANTs1 0.37
[153,] cc1.21
[154.1 SCARE2 .
E 153.1 gAD21.15?
1190.1 FT$
(157,1 mer.1
[159,1
(159,1 cRrF2 .
1150,1 UGC0
[151,) P28511
[IVA MHZ
[163,1 CDR1
(164.) 01381.3 .
(165,) ETN1
c196.1 MICA
[107,1 = FT01
(168,) 81400 '
=
84
CA 02631236 2008-05-26
WO 2007/072225
PCT/1B2006/004048
E169,1 tAP1211
PCO2
1111,1 coLZA2
(17211 C$21
(173,1 Kam
t/74,J
1175,1 CTSD
=
t1761 artpx3A4
117711 csnyi
0.7E10 s18DA4
[1790 CALDI
TIR0.1 CTGP
rino MEC
= [1624 tAGMS
[IRS,/ rSTL1
=
Litr4r) SCTR
(185,1 =PRA
(1815,1 CoPES
[157,1 DIPA
[1.89,) SKARCD3
[lErgrj XVp
[141,1 V13745
t1910 s1ODA13
[192,1 me=
=
=
CA 02631236 2008-05-26
WO 2007/072225
PCT/IB2006/004048
Table 22. Vincristine biomarkers.
Gene Correlation Probe Sequence
[1,] SLC25A5 0.32 TCCTGTACTTGTCCTCAGCTTGGGC
[2,] RPL10 0.38 GCCCCACTGGACAACACTGATTCCT
[3,] RPL12 0.31 TGCCTGCTCCTGTACTTGTCCTCAG
[4,1 RPS4X 0.39 AAATGTTTCCTTGTGCCTGCTCCTG
[5,) EIF5A 0.31 TCCTGTACTTGTCCTCAGCTTGGGC
[6,] BLMH 0.32 AAGCCTATACGTTTCTGTGGAGTAA
[7,] TBCA 0.3 AeTTGTCCTCAGCTTGGGCTTCTTC
[8,] MDH2 0.34 TCCTGTACTTGTCCTCAGCTTGGGC
[9,] 5100A4 0.32 TGGACCCCACTGGCTGAGAATCTGG
[10,] C14orf139 0.3 TTGGACATCTCTAGTGTAGCTGCCA
Table 23. Cisplatin biomarkers.
Gene Correlation Probe Sequence
[1,] C1QR1 0.3 CACCCAGCTGGTCCTGTGGATGGGA
[2,] SLA 0.37 TGCCTGCTCCTGTACTTGTCCTCAG ,
(3,1 PTPN7 0.31 ACTTGTCCTCAGCTTGGGCTTCTIC
[4,] ZNFN1A1 0.33 CACCCAGCTGGTCCTGTGGATGGGA
[5,] CENTB1 0.37 TTGGACATCTCTAGTGTAGCTGCCA
[6,] IFT16 0.31 TCCTCCATCACCTGAAACACTGGAC
[7,] ARHGEF6 0.35 TGCCTGCTCCTGTACTTGTCCTCAG
[8,1 SEC31L2 0.32 AAGCCTATACGTTTCTGTGGAGTAA
[9,] CD3Z 0.32 TTGGACATCTCTAGTGTAGCTGCCA
[10,] GZMB 0.3 TCCTCCATCACCTGAAACACTGGAC
[11,] CD3D 0.34 TCCTCCATCACCTGAAACACTGGAC
[12,1 MAP4K1 0.32 CACCCAGCTGGTCCTGTGGATGGGA
[13,] GPR65 0.39 CACCCAGCTGGTCCTGTGGATGGGA
[14,] PRF1 0.31 TCCTTGTGCCTGCTCCTGTACTTGT
[15,] ARHGAP15 0.35 CACCCAGCTGGTCCTGTGGATGGGA
[16,] TM6SF1 0.41 TGCCTGCTCCTGTACTTGTCCTCAG
[17,] TCF4 0.4 AAATGTTTCCTTGTGCCTGCTCCTG
Table 24. Etoposide biomarkers.
Gene Correlation Probe Sequence
[1,] C099 0.3 AAGCCTATACGTTTCTGTGGAGTAA
[2,] INSIG1 0.35 TCCTTGTGCCTGCTCCTGTACTTGT
[3,] PRG1 0.34 GCCCCACTGGACAACACTGATTCCT
[4,] MUF1 0.35 AAGCCTATACGTTTCTGTGGAGTAA
[5,] SLA 0.37 CACCCAGCTGGTCCTGTGGATGGGA
[6,] SSBP2 0.37 TGGACCCCACTGGCTGAGAATCTGG
[7,] GNB5 0.35 TCCTTGTGCCTGCTCCTGTACTTGT
[8,] MFNG 0.33 GCCCCACTGGACAACACTGATTCCT
[9,] PSMB9 0.31 ' =AAGCCTATACGTTTCTGTGGAGTAA
[10,] EVIZA 0.41 TCCTCCATCACCTGAAACACTGGAC
[11,] PTPN7 0.3 AAGCCTATACGTTTCTGTGGAGTAA
[12,] PTGER4 0.3 TGCCTGCTCCTGTACTTGTCCTCAG
[13,] CXorf9 0.3 GCCCCACTGGACAACACTGATTCCT
[14,] ZNFN1A1 0.35 ACTTGTCCTCAGCTTGGGCTTCTTC
[15,] CENTB1 0.3 TGGACCCCACTGGCTGAGAATCTGG
[16,] NAP1L1 0.31 TCCTCCATCACCTGAAACACTGGAC
[17,] HLA-DRA 0.34 TGCCTGCTCCTGTACTTGTCCTCAG
[18,] IF116 0.38 CACCCAGCTGGTCCTGTGGATGGGA
[19,] ARHGEF6 0.33 TGGACCCCACTGGCTGAGAATCTGG
[20,] PSCDBP 0.4 AAGCCTATACGTTTCTGTGGAGTAA
[21,1 SELPLG 0.35 TTGGACATCTCTAGTGTAGCTGCCA
[22,1 SEC31L2 0.42 AAATGTTTCCTTGTGCCTGCTCCTG
86
CA 02631236 2008-05-26
W02007/072225
PCT/1132006/004048
[23,] CD3Z - 0.36 TGCCTGCTCCTGTACTTGTCCTCAG
[24,] SH2D1A 0.33 CACCCAGCTGGTCCTGTGGATGGGA
[25,] GZMB 0.34 TGGACCCCACTGGCTGAGAATCTGG
[26,1 SCN3A 0.3 GCCCCACTGGACAACACTGATTCCT
[27,1 RAFTLIN 0.39 TCCTCCATCACCTGAAACACTGGAC
[28,] DOCK2 0.33 TGCCTGCTCCTGTACTTGTCCTCAG
[29,] CD3D 0.31 ACTTGTCCTCAGCTTGGGCTTCTTC
[30,] ZAP70 0.35 TCCTCCATCACCTGAAACACTGGAC
[31,] GPR65 0.35 TGGACCCCACTGGCTGAGAATCTGG
[32,] PRF1 0.32 TGGACCCCACTGGCTGAGAATCTGG
[33,1 ARHGAP15 0.32 ACTTGTCCTCAGCTTGGGCTTCTTC
[34,] NOTCH]. 0.31 TGCCTGCTCCTGTACTTGTCCTCAG
[35,] UBASH3A 0.32 ACTTGTCCTCAGCTTGGGCTTCTTC
Table 25. Azaguanine biomarkers.
Gene Correlation Probe Sequence
[1,] SRM 0.32 TGCCTGCTCCTGTACTTGTCCTCAG
[2,] SCARB1 0.4 TTGGACATCTCTAGTGTAGCTGCCA
[3,] SIAT1 0.31 AAATGTTTCCTTGTGCCTGCTCCTG
[4,1 CUGBP2 0.37 TGGACCCCACTGGCTGAGAATCTGG
[5,] WASPIP 0.44 TCCTGTACTTGTCCTCAGCTTGGGC
[6,] ITM2A 0..31 AAGCCTATACGTTTCTGTGGAGTAA
[7,1 PALM2-AKAP2 0.31 ACTTGTCCTCAGCTTGGGCTTCTTC
[8,1 LNK 0.43 TTGGACATCTCTAGTGTAGCTGCCA
[9,] FCGR2A 0.3 TGCCTGCTCCTGTACTTGTCCTCAG
[10,] RUNX3 0.43 TCCTGTACTTGTCCTCAGCTTGGGC
[11,] EVI2A 0.4 AAATGTTTCCTTGTGCCTGCTCCTG
[12,] BTN3A3 0.4 ACTTGTCCTCAGCTTGGGCTTCTTC
[13,] LCP2 0.34 TCCTTGTGCCTGCTCCTGTACTTGT
[14,] BCHE 0.35 TCCTCCATCACCTGAAACACTGGAC
[15,] LY96 0.47 TGCCTGCTCCTGTACTTGTCCTCAG
[16,] LOP]. 0.42 ACTTGTCCTCAGCTTGGGCTTCTTC
[17,] IFI16 0.33 CACCCAGCTGGTCCTGTGGATGGGA
[18,] MCAM 0.37 TTGGACATCTCTAGTGTAGCTGCCA
[19,] MEF2C 0.41 CACCCAGCTGGTCCTGTGGATGGGA
[20,] FYN 0.31 TCCTGTACTTGTCCTCAGCTTGGGC
[21,] C1orf38 0.37 AAGCCTATACGTTTCTGTGGAGTAA
[22,] FCGR2C 0.34 TGCCTGCTCCTGTACTTGTCCTCAG
[23,] TNIK 0.35 AAGCCTATACGTTTCTGTGGAGTAA
[24,] AMPD2 0.3 TCCTGTACTTGTCCTCAGCTTGGGC
[25,1 SEPT6 0.41 AAATGTTTCCTTGTGCCTGCTCCTG
[26,] RAFTLIN 0.39 TCCTTGTGCCTGCTCCTGTACTTGT
[27,} SLC43A3 0.52 CACCCAGCTGGTCCTGTGGATGGGA
[28,] LPXN 0.54 AAGCCTATACGTTTCTGTGGAGTAA
[29,] CKIP-1 0.33 TCCTGTACTTGTCCTCAGCTTGGGC
[30,] FLJ10539 0.33 TCCTTGTGCCTGCTCCTGTACTTGT
[31,1 FLJ35036 0.36 AAGCCTATACGTTTCTGTGGAGTAA
[32,] DOCK10 0.3 GCCCCACTGGACAACACTGATTCCT
[33,] TRPV2 0.31 ACTTGTCCTCAGCTTGGGCTTCTTC
[34,] IFRG28 0.3 TCCTTGTGCCTGCTCCTGTACTTGT
[35,] LEFT 0.31 ACTTGTCCTCAGCTTGGGCTTCTTC =
[36,] ADAMTS1 0.36 TGGACCCCACTGGCTGAGAATCTGG
Table 26. Carboplatin biomarkers.
Gene Correlation Probe Sequence
[1,] ITGA5 0.43 AAATGTTTCCTTGTGCCTGCTCCTG
[2,] TNFAIP3 0.4 TGCCTGCTCCTGTACTTGTCCTCAG
87
CA 02631236 2008-05-26
WO 2007/072225
PCT/IB2006/004048
[3,] WINT5A 0.34 TCCTCCATCACCTGAAACACTGGAC
[4,] FOXF2 0.36 TGCCTGCTCCTGTACTTGTCCTCAG
[5,] LOC94105 0.32 AAATGTTTCCTTGTGCCTGCTCCTG
[6,] IF116 0.38 TCCTCCATCACCTGAAACACTGGAC
[7,] LRRN3 0.33 TTGGACATCTCTAGTGTAGCTGCCA
[8,] DOCK10 0.4 TCCTGTACTTGTCCTCAGCTTGGGC
[9,] LEPRE1 0.32 GCCCCACTGGACAACACTGATTCCT
[10,] ADAMTS1 0.34 TGGACCCCACTGGCTGAGAATCTGG
Table 27. Adriamycin biomarkers.
Gene Correlation Probe Sequence
[1,] CD99 0.41 AAGCCTATACGTTTCTGTGGAGTAA
[2,] ALDOC 0.31 . TCCTTGTGCCTGCTCCTGTACTTGT
[3,] SLA 0.35 TGCCTGCTCCTGTACTTGTCCTCAG
[4,] SSBP2 0.34 TCCTCCATCACCTGAAACACTGGAC
[5,] IL2RG 0.38 TCCTTGTGCCTGCTCCTGTACTTGT
[6,] CXorf9 0.32 TGGACCCCACTGGCTGAGAATCTGG
[7,] RHOH 0.31 ACTTGTCCTCAGCTTGGGCTTCTTC
[8,] ZNFN1A1 0.43 TTGGACATCTCTAGTGTAGCTGCCA
[9,] CENTB1 0.36 AAGCCTATACGTTTCTGTGGAGTAA
[10,] MAP4K1 0.35 TCCTCCATCACCTGAAACACTGGAC
[11,] CD3G 0.31 AAATGTTTCCTTGTGCCTGCTCCTG
[12,] CCR9 0.34 CACCCAGCTGGTCCTGTGGATGGGA
[13,] CXCR4 0.3 TCCTTGTGCCTGCTCCTGTACTTGT
[14,] ARHGEF6 0.31 TCCTCCATCACCTGAAACACTGGAC
[15,] SELPLG 0.31 TGGACCCCACTGGCTGAGAATCTGG
[16,] SEC31L2 0.33 TGCCTGCTCCTGTACTTGTCCTCAG
[17,] CD3Z 0.37 ACTTGTCCTCAGCTTGGGCTTCTTC
[18,] SH2D1A 0.37 TTGGACATCTCTAGTGTAGCTGCCA
[19,] CD1A 0.4 AAGCCTATACGTTTCTGTGGAGTAA.
[20,] LAIR1 0.39 AAGCCTATACGTTTCTGTGGAGTAA
[21,] TRB@ 0.34 TCCTCCATCACCTGAAACACTGGAC
[22,1 CD3D 0.33 TCCTTGTGCCTGCTCCTGTACTTGT
[23,] WBSCR20C 0.34 ACTTGTCCTCAGCTTGGGCTTCTTC
[24,] ZAP7O 0.33 TCCTGTACTTGTCCTCAGCTTGGGC
[25,] IFI44 0.32 TGCCTGCTCCTGTACTTGTCCTCAG
[26,] GPR65 0.31 AAGCCTATACGTTTCTGTGGAGTAA
[27,] AIF1 0.3 CACCCAGCTGGTCCTGTGGATGGGA
[28,] ARHGAP15 0.37 TCCTGTACTTGTCCTCAGCTTGGGC
[29,] NARF 0.3 TCCTCCATCACCTGAAACACTGGAC
[30,] PACAP 0.32 CACCCAGCTGGTCCTGTGGATGGGA
Table 28. Aclarubicin biomarkers.
Gene Correlation Probe Sequence
[1,] RPL12 0.3 AAATGTTTCCTTGTGCCTGCTCCTG
[2,1 RPLP2 0.37 TTGGACATCTCTAGTGTAGCTGCCA
[3,1 MYB 0.31 TCCTTGTGCCTGCTCCTGTACTTGT
[4,] ZNFN1A1 0.34 AAATGTTTCCTTGTGCCTGCTCCTG
(5,1 SCAP1 0.33 TGCCTGCTCCTGTACTTGTCCTCAG
[6,] STAT4 0.31 AAATGTTTCCTTGTGCCTGCTCCTG
[7,] SP140 0.4 AAGCCTATACGTTTCTGTGGAGTAA
[8,] AMPD3 0.3 TGCCTGCTCCTGTACTTGTCCTCAG
[9,] TNFAIP8 0.4 AAGCCTATACGTTTCTGTGGAGTAA
[10,].DDX18 0.31 TCCTTGTGCCTGCTCCTGTACTTGT
(11,1 TAF5 0.3 TCCTTGTGCCTGCTCCTGTACTTGT
[12,] RPS2 0.34 CACCCAGCTGGTCCTGTGGATGGGA
[13,] DOCK2 0.32 AAGCCTATACGTTTCTGTGGAGTAA
88
CA 02631236 2008-05-26
W02007/072225
PCT/IB2006/004048
[14,] GPR65 0.35 AAGCCTATACGTTTCTGTGGAGTAA
[15,] ROXA9 0.33 TCCTTGTGCCTGCTCCTGTACTTGT
[16,1 FLJ12270 0.31 AAATGTTTCCTTGTGCCTGCTCCTG
[17,] HNRPD 0.4 ACTTGTCCTCAGCTTGGGCTTCTTC
Table 29. Mitoxantrone biomarkers.
Gene Correlation Probe Sequence
[1,1 PGAM1 0.32 TGCCTGCTCCTGTACTTGTCCTCAG
[2,] DPYSL3 0.36 AAATGTTTCCTTGTGCCTGCTCCTG
[3,] INSIG1 0.32 TCCTTGTGCCTGCTCCTGTACTTGT
[4,] GJA1 0.31 TTGGACATCTCTAGTGTAGCTGCCA
[5,] BNIP3 0.31 TTGGACATCTCTAGTGTAGCTGCCA
[6,] PRG1 0.39 GCCCCACTGGACAACACTGATTCCT
[7,] G6PD 0.34 TGCCTGCTCCTGTACTTGTCCTCAG
[8,] PLOD2 0.34 GCCCCACTGGACAACACTGATTCCT
[9,] LOXL2 0.31 TCCTTGTGCCTGCTCCTGTACTTGT
[10,] SSBP2 0.36 TCCTCCATCACCTGAAACACTGGAC
[11,1 C1orf29 0.35 TCCTTGTGCCTGCTCCTGTACTTGT
[12,] PDX 0.35. TCCTTGTGCCTGCTCCTGTACTTGT
[13,] STC1 0.39 TCCTGTACTTGTCCTCAGCTTGGGC
[14,] TNFRSF1A 0.34 AAATGTTTCCTTGTGCCTGCTCCTG
[15,] NCOR2 0.3 TCCTCCATCACCTGAAACACTGGAC
[16,] NAP1L1 0.32 TCCTTGTGCCTGCTCCTGTACTTGT
[17,] 10C94 105 0.34 AAGCCTATACGTTTCTGTGGAGTAA
[18,] ARHGEF6 0.34 TCCTCCATCACCTGAAACACTGGAC
[19,] GATA3 0.35 TCCTTGTGCCTGCTCCTGTACTTGT
[20,] TFPI 0.31 TCCTGTACTTGTCCTCAGCTTGGGC
[21,] CD3Z 0.37 AAGCCTATACGTTTCTGTGGAGTAA
[22,] AH1Q 0.33 GCCCCACTGGACAACACTGATTCCT
[23,] MAP1B 0.34 TGCCTGCTCCTGTACTTGTCCTCAG
[24,] CD3D 0.31 TCCTTGTGCCTGCTCCTGTACTTGT
[25,] BCAT1 0.32 TCCTGTACTTGTCCTCAGCTTGGGC
[26,] IFI44 0.33 TGGACCCCACTGGCTGAGAATCTGG
[27,] CUTC 0.33 AAATGTTTCCTTGTGCCTGCTCCTG
[28,] NAP1L2 0.33 AAGCCTATACGTTTCTGTGGAGTAA
[29,] N4E7 0.35 AAATGTTTCCTTGTGCCTGCTCCTG
[30,] FLJ21159 0.33 TCCTGTACTTGTCCTCAGCTTGGGC
Table 30. Mitomycin biomarkers.
Gene Correlation Probe Sequence
[1,] STC1 0-34 TGCCTGCTCCTGTACTTGTCCTCAG
[2,] GPR65 0-32 GCCCCACTGGACAACACTGATTCCT
[3,1 DOCK10 0.35 ACTTGTCCTCAGCTTGGGCTTCTTC
[4,] FAM46A 0.36 TCCTTGTGCCTGCTCCTGTACTTGT
[5,] L0054103 0.39 ACTTGTCCTCAGCTTGGGCTTCTTC
Table 31. Paclitaxel (Taxol) biomarkers.
Gene Correlation Probe Sequence
[1,] RPL10 0.31 TCCTCCATCACCTGAAACACTGGAC
[2,] RPS4X 0.31 TCCTCCATCACCTGAAACACTGGAC
[3,] DKC1 0.3 TCCTTGTGCCTGCTCCTGTACTTGT
[4,1 DKFZP564C186 0.32 ACTTGTCCTCAGCTTGGGCTTCTTC
[5,] PRP19 0.31 TGCCTGCTCCTGTACTTGTCCTCAG
[6,] RAB9P40 0.33 GCCCCACTGGACAACACTGATTCCT
[7,] HSA9761 0.37 AAATGTTTCCTTGTGCCTGCTCCTG
[8,] GMDS 0.3 AAATGTTTCCTTGTGCCTGCTCCTG
89
CA 02631236 2008-05-26
WO 2007/072225
PCT/IB2006/004048
[9,] CEPI 0.3 AAATGTTTCCTTGTGCCTGCTCCTG
[10,] IL13RA2 0.34 AAATGTTTCCTTGTGCCTGCTCCTG
[11,] MAGEB2 0.41 ACTTGTCCTCAGCTTGGGCTTCTTC
[12,] HMGN2 0.35 CACCCAGCTGGTCCTGTGGATGGGA
[13,] ALMS1 0.3 TCCTCCATCACCTGAAACACTGGAC
[14,] GPR65 0.31 TGCCTGCTCCTGTACTTGTCCTCAG
[15,] F1J10774 0.31 TGGACCCCACTGGCTGAGAATCTGG
[16,] NOL8 0.31 = TGCCTGCTCCTGTACTTGTCCTCAG
[17,] DAZAPI 0.32 TGCCTGCTCCTGTACTTGTCCTCAG
[18,] SLC25A15 0.31 TTGGACATCTCTAGTGTAGCTGCCA
[19,] PAF53 0.36 TCCTCCATCACCTGAAACACTGGAC
[20,] PITPNC1 0.33 TCCTCCATCACCTGAAACACTGGAC
[21,] SPANXC 0.3 TGGACCCCACTGGCTGAGAATCTGG
[22,] KIAA1393 0.33 CACCCAGCTGGTCCTGTGGATGGGA
Table 32. Gemcitabine (Gemzar) biomarkers.
Gene Correlation Probe Sequence
[1,] UBE2L6 0.38 CACCCAGCTGGTCCTGTGGATGGGA
[2,] TAFT 0.33 CACCCAGCTGGTCCTGTGGATGGGA
[3,] F2R 0.3 TCCTGTACTTGTCCTCAGCTTGGGC
[4,] PSMB9 0.31 TGCCTGCTCCTGTACTTGTCCTCAG
[5,] IL7R 0.31 AAGCCTATACGTTTCTGTGGAGTAA
[6,] TNFAIP8 0.33 AAGCCTATACGTTTCTGTGGAGTAA
[7,] HLA-C 0.33 TGGACCCCACTGGCTGAGAATCTGG
[8,] IFI44 0.31 TGGACCCCACTGGCTGAGAATCTGG
Table 33. Taxotere (docetaxel) biomarkers.
Gene Correlation Probe Sequence
[1,] ANP32B 0.45 GCCCCACTGGACAACACTGATTCCT
[2,] GTF3A 0.31 TTGGACATCTCTAGTGTAGCTGCCA
[3,1 TRIM14 0.31 ACTTGTCCTCAGCTTGGGCTTCTTC
[4,] SKP2 0.33 GCCCCACTGGACAACACTGATTCCT
[5,] TRIP13 0.36 TCCTGTACTTGTCCTCAGCTTGGGC
[6,] RFC3 0.45 GCCCCACTGGACAACACTGATTCCT
[7,] CASP7 0.32 TGCCTGCTCCTGTACTTGTCCTCAG
[8,] TXN 0.36 AAGCCTATACGTTTCTGTGGAGTAA
[9,] MCM5 0.34 AAATGTTTCCTTGTGCCTGCTCCTG
[10,] PTGES2 0.39 AAATGTTTCCTTGTGCCTGCTCCTG
[11,1 OBFC1 0.37 TGGACCCCACTGGCTGAGAATCTGG
[12,] EPB41L4B 0.32 GCCCCACTGGACAACACTGATTCCT
[13,1 CALML4 0.31 TCCTCCATCACCTGAAACACTGGAC
Table 34. Dexamethasone biomarkers.
Gene Correlation Probe Sequence
[1,] IFITM2 0.38 ATATATGGACCTAGCTTGAGGCAAT
[2,] UBE2L6 0.32 AAGCCTATACGTTTCTGTGGAGTAA
[3,] ITM2A 0.38 CACCCAGCTGGTCCTGTGGATGGGA
[4,] IL2RG 0.36 TCCTCCATCACCTGAAACACTGGAC
[5,1 GPRASP1 0.36 TCCTGTACTTGTCCTCAGCTTGGGC
[6,] PTPN7 0.31 TCCTTGTGCCTGCTCCTGTACTTGT
[7,1 CXorf9 0.36 GCCCCACTGGACAACACTGATTCCT
[8,] RHOH 0.33 TGCCTGCTCCTGTACTTGTCCTCAG
[9,]=GIT2 0.31 ACTTGTCCTCAGCTTGGGCTTCTTC
[10õ] ZNFN1A1 0.35 TCCTTGTGCCTGCTCCTGTACTTGT
[11,] CEP1 0.31 CACCCAGCTGGTCCTGTGGATGGGA
[12,] MAP4K1 0.3 AAGCCTATACGTTTCTGTGGAGTAA
=
[13,] CCR7 0.33 AAATGTTTCCTTGTGCCTGCTCCTG
CA 02631236 2008-05-26
WO 2007/072225
PCT/IB2006/004048
[14,] CD3G 0.35 CACCCAGCTGGTCCTGTGGATGGGA
[15,] UCP2 0.3 AAGCCTATACGTTTCTGTGGAGTAA
[16,] GATA3 0.37 TGGACCCCACTGGCTGAGAATCTGG
[17,] CDKN2A 0.32 TCCTGTACTTGTCCTCAGCTTGGGC
[18,] TARP 0.3 .GCCCCACTGGACAACACTGATTCCT
[19,] LAIR1 0.34 TTGGACATCTCTAGTGTAGCTGCCA
. [20,] SH2D1A 0.34 TCCTTGTGCCTGCTCCTGTACTTGT
[21,] SEPT6 0.34 TGCCTGCTCCTGTACTTGTCCTCAG
[22,] HA-I 0.34 TCCTTGTGCCTGCTCCTGTACTTGT
[23,] CD3D 0.32 TCCTCCATCACCTGAAACACTGGAC
[24,] LST1 0.39 CACCCAGCTGGTCCTGTGGATGGGA
[25,] AIF1 0.35 AAGCCTATACGTTTCTGTGGAGTAA
[26,] ADA 0.33 TGCCTGCTCCTGTACTTGTCCTCAG
[27,] DATF1 0.41 CACCCAGCTGGTCCTGTGGATGGGA
[28,] AREGAP15 0.3 TCCTGTACTTGTCCTCAGCTTGGGC
[29,] PLACS 0.31 CACCCAGCTGGTCCTGTGGATGGGA .
[30,] CECR1 0.31 GCCCCACTGGACAACACTGATTCCT
[31,] LOC81558 0.33 TGGACCCCACTGGCTGAGAATCTGG
[32,] EHD2 0.37 ACTTGTCCTCAGCTTGGGCTTCTTC
Table 35. Ara-C (Cytarabine hydrochloride) biomarkers.
Gene Correlation Probe Sequence
[1,] ITM2A 0.32 TGGACCCCACTGGCTGAGAATCTGG
[2,] RHOH 0.31 AAATGTTTCCTTGTGCCTGCTCCTG
[3,] PRIM1 0.3 TCCTCCATCACCTGAAACACTGGAC
[4,] CENTB1 0.31 TCCTTGTGCCTGCTCCTGTACTTGT
[5,] NAP1L1 0.31 GCCCCACTGGACAACACTGATTCCT
[6,] ATP5G2 0.31 TCCTCCATCACCTGAAACACTGGAC
[7,] GATA3 0.33 AAATGTTTCCTTGTGCCTGCTCCTG
[8,] PRKCQ 0.32 AAGCCTATACGTTTCTGTGGAGTAA
[9,] SH2D1A 0.3 GCCCCACTGGACAACACTGATTCCT
[10,] SEPT6 0.42 ACTTGTCCTCAGCTTGGGCTTCTTC
[11,] NME4 0.33 ACTTGTCCTCAGCTTGGGCTTCTTC
[12,] CD3D 0.31 AAGCCTATACGTTTCTGTGGAGTAA
[13,] CD1E 0.32 TGGACCCCACTGGCTGAGAATCTGG
[14,] ADA 0.34 GCCCCACTGGACAACACTGATTCCT
[15,] FHOD1 0.31 CACCCAGCTGGTCCTGTGGATGGGA
Table 36. Methylprednisolone biomarkers.
Gene Correlation Probe Sequence
[1,] CD99 0.31 GCCCCACTGGACAACACTGATTCCT
[2,] ARHGDIB 0.31 TGCCTGCTCCTGTACTTGTCCTCAG
[3,] ITM2A 0_35 GCCCCACTGGACAACACTGATTCCT
[4,] LGALS9 0.43 TCCTCCATCACCTGAAACACTGGAC
[5,1 INPP5D 0.34 = TGGACCCCACTGGCTGAGAATCTGG
[6,] SATB1 0.32 TCCTTGTGCCTGCTCCTGTACTTGT
[7,] TFDP2 0.4 AAATGTTTCCTTGTGCCTGCTCCTG
[8,] SLA 0.31 TGGACCCCACTGGCTGAGAATCTGG
[9,] IL2RG 0.3 TGCCTGCTCCTGTACTTGTCCTCAG
[10,] MENG 0.3 TGCCTGCTCCTGTACTTGTCCTCAG
(11,j SELL 0.33 AAATGTTTCCTTGTGCCTGCTCCTG
[12,] CDW52 0.33 TCCTCCATCACCTGAAACACTGGAC
[13,] LRMP 0.32 TCCTGTACTTGTCCTCAGCTTGGGC
[14,] ICAM2 0.38 CACCCAGCTGGTCCTGTGGATGGGA
[15,] RIMS3 0.36 TGCCTGCTCCTGTACTTGTCCTCAG
[16,] PTPN7 0.39 TGGACCCCACTGGCTGAGAATCTGG
[17,] ARHGAP25 0.37 TCCTGTACTTGTCCTCAGCTTGGGC
91
CA 02631236 2008-05-26
WO 2007/072225
PCT/IB2006/004048
[18,] LCK 0.3 TCCTCCATCACCTGAAACACTGGAC
[19,] CXorf9 0.3 TTGGACATCTCTAGTGTAGCTGCCA
[20,] RHOH 0.51 AAGCCTATACGTTTCTGTGGAGTAA
[21,] GIT2 0.33 ACTTGTCCTCAGCTTGGGCTTCTTC
[22,] ZNFN1A1 0.53 TCCTTGTGCCTGCTCCTGTACTTGT
[23,] CENTB1 0.36 TCCTCCATCACCTGAAAGACTGGAC
[24,] L0P2 0.34 TCCTGTACTTGTCCTCAGCTTGGGC
[25,] S9I1 0.3 TCCTGTACTTGTCCTCAGCTTGGGC
[26,] GZMA 0.31 AAGCCTATACGTTTCTGTGGAGTAA
[27,] CEP1 0.37 AAGCCTATACGTTTCTGTGGAGTAA
[28,] CD8A 0.38 TGGACCCCACTGGCTGAGAATCTGG
[29,] SCAP1 0.32 TCCTCCATCACCTGAAACACTGGAC
[30,] CD2 0.48 GCCCCACTGGACAACACTGATTCCT
[31,] VAV1 0.41 ACTTGTCCTCAGCTTGGGCTTCTTC
[32,] MAP4K1 0.36 TCCTGTACTTGTCCTCAGCTTGGGC
[33,] CCR7 0.37 ACTTGTCCTCAGCTTGGGCTTCTTC
[34,) C6orf32 0.38 TCCTTGTGCCTGCTCCTGTACTTGT
[35,] ALOX158 0.43 TGCCTGCTCCTGTACTTGTCCTCAG
[36,] BRDT 0.33 AAGCCTATACGTTTCTGTGGAGTAA
[37,) CD3G 0.51 AAGCCTATACGTTTCTGTGGAGTAA
[38,] LTB 0.32 ACTTGTCCTCAGCTTGGGCTTCTTC
[39,1 NVL 0.31 TTGGACATCTCTAGTGTAGCTGCCA
[40,1.RASGRP2 0.35 TGCCTGCTCCTGTACTTGTCCTCAG
[41,] LCP1 0.34 AAATGTTTCCTTGTGCCTGCTCCTG
[42,] CXCR4 0.3 AAGCCTATACGTTTCTGTGGAGTAA
[43,] PRKD2 0.33 CACCCAGCTGGTCCTGTGGATGGGA
[44,] GATA3 0.39 TCCTGTACTTGTCCTCAGCTTGGGC
[45,] KIAA0922 0.36 GCCCCACTGGACAACACTGATTCCT
[46,1 TARP 0.49 TCCTCCATCACCTGAAACACTGGAC
[47,] 5EC31L2 0.32 ACTTGTCCTCAGCTTGGGCTTCTTC
[48,] PRKCQ 0.37 TTGGACATCTCTAGTGTAGCTGCCA
[49,] SH2D1A 0.33 AAGCCTATACGTTTCTGTGGAGTAA
[50,] CHRNA3 0.5 AAGCCTATACGTTTCTGTGGAGTAA
[51,) CD1A 0.44 AAGCCTATACGTTTCTGTGGAGTAA
[52,1 LST1 0.36 CACCCAGCTGGTCCTGTGGATGGGA
[53,1 LAIR1 0.47 CACCCAGCTGGTCCTGTGGATGGGA
[54,] CACNA1G 0.33 GCCCCACTGGACAACACTGATTCCT
[55,] TRB@ 0.31 ACTTGTCCTCAGCTTGGGCTTCTTC
[56,] SEPT6 0.33 TCCTTGTGCCTGCTCCTGTACTTGT
[57,] RA-1 0.42 CACCCAGCTGGTCCTGTGGATGGGA
[58,1 00CK2 0.32 TCCTGTACTTGTCCTCAGCTTGGGC
[59,] CD3D 0.41 TCCTGTACTTGTCCTCAGCTTGGGC
[60,] TRD@ 0.38 TGCCTGCTCCTGTACTTGTCCTCAG
[61,1 T3JAM 0.37 TGCCTGCTCCTGTACTTGTCCTCAG
[62,] FNBP1 0.37 TCCTGTACTTGTCCTCAGCTTGGGC
[63,] CD6 0.4 CACCCAGCTGGTCCTGTGGATGGGA
[64,] AIF1 0.31 TGCCTGCTCCTGTACTTGTCCTCAG
[65,] FOLH1 0.45 TCCTGTACTTGTCCTCAGCTTGGGC
[66,] CD1E 0.58 CACCCAGCTGGTCCTGTGGATGGGA
[67,1 LY9 0.39 TCCTTGTGCCTGCTCCTGTACTTGT
[68,1 ADA 0.39 AAATGTTTCCTTGTGCCTGCTCCTG
[69,1 CDKL5 0.44 GCCCCACTGGACAACACTGATTCCT
[70,] TRIM 0.38 AAGCCTATACGTTTCTGTGGAGTAA
[71,] DATF1 0.31 ACTTGTCCTCAGCTTGGGCTTCTTC
[72,] RGC32 0.51 TCCTTGTGCCTGCTCCTGTACTTGT
[73,1 ARHGAP15 0.34 CACCCAGCTGGTCCTGTGGATGGGA
[74,1 NOTCH' 0.36 TCCTTGTGCCTGCTCCTGTACTTGT
92
=
CA 02631236 2008-05-26
WO 2007/072225
PCT/IB2006/004048
[75,] BIN2 0.31 AAATGTTTCCTTGTGCCTGCTCCTG
[76,1 SEMA4G 0.35 AAGCCTATACGTTTCTGTGGAGTAA
[77,7 DPEP2 0.33 CACCCAGCTGGTCCTGTGGATGGGA
[78,] CECR1 0.36 TCCTGTACTTGTCCTCAGCTTGGGC
[79,] BCL11B 0.33 TGCCTGCTCCTGTACTTGTCCTCAG
[80,] STAG3 0.41 TTGGACATCTCTAGTGTAGCTGCCA
[81,] GALNT6 0.32 TGCCTGCTCCTGTACTTGTCCTCAG
(82,) UBASH3A 0.3 AAATGTTTCCTTGTGCCTGCTCCTG
[83,] PHEMX 0.38 TCCTCCATCACCTGAAACACTGGAC
[84,] FLJ13373 0.34 TCCTTGTGCCTGCTCCTGTACTTGT
(85,7 LEF1 0.49 TCCTCCATCACCTGAAACACTGGAC
[86,] IL21R 0.42 TTGGACATCTCTAGTGTAGCTGCCA
[87,] MGC17330 0.33 TCCTTGTGCCTGCTCCTGTACTTGT
[88,] AKAP13 0.53 TCCTTGTGCCTGCTCCTGTACTTGT
[89,] GIMAP5 0.34 AAATGTTTCCTTGTGCCTGCTCCTG
Table 37. Methotrexate biomarkers.
Gene Correlation Probe Sequence
[1,] PRPF8 0.34 TCCTCCATCACCTGAAACACTGGAC
[2,] RPL18 0.34 AAGCCTATACGTTTCTGTGGAGTAA
[3,1 GOT2 0.31 CACCCAGCTGGTCCTGTGGATGGGA
[4,] RPL13A 0.31 TCCTGTACTTGTCCTCAGCTTGGGC
[5,] RPS15 0.39 CACCCAGCTGGTCCTGTGGATGGGA
[6,] RPLP2 0.32 GCCCCACTGGACAACACTGATTCCT
[7,] CSDA 0.39 GCCCCACTGGACAACACTGATTCCT
[8,] KHDRBS1 0.32 TCCTCCATCACCTGAAACACTGGAC
[9,] SNRPA 0.31 TCCTGTACTTGTCCTCAGCTTGGGC
[10,] IMPDH2 0.39 AAATGTTTCCTTGTGCCTGCTCCTG
[11,] RPS19 0.47 AAATGTTTCCTTGTGCCTGCTCCTG
[12,] NUP88 0.36 . CACCCAGCTGGTCCTGTGGATGGGA
[13,] ATP5D 0.33 TGCCTGCTCCTGTACTTGTCCTCAG
(14,] PCBP2 0.32 AAATGTTTCCTTGTGCCTGCTCCTG
[15,] ZNF593 0.4 AAATGTTTCCTTGTGCCTGCTCCTG
[16,] 1iSU79274 0.32 TGGACCCCACTGGCTGAGAATCTGG
[17,] PRIM1 0.3 CACCCAGCTGGTCCTGTGGATGGGA
[18,] PFDN5 0.33 TCCTCCATCACCTGAAACACTGGAC
[19,7 OXAlL 0.37 CACCCAGCTGGTCCTGTGGATGGGA
[20,] ATIC 0.31 ACTTGTCCTCAGCTTGGGCTTCTTC
[21,] CIAPIN1 0.34 ACTTGTCCTCAGCTTGGGCTTCTTC
[22,] RPS2 0.32 CACCCAGCTGGTCCTGTGGATGGGA
[23,] PCCB 0.36 GCCCCACTGGACAACACTGATTCCT
[24,7 SHMT2 0.34 ACTTGTCCTCAGCTTGGGCTTCTTC
[25,] RPI,P0 0.35 AAGCCTATACGTTTCTGTGGAGTAA
[26,] HNRPA1 0.35 TGGACCCCACTGGCTGAGAATCTGG
[27,] STOML2 0.32 TGCCTGCTCCTGTACTTGTCCTCAG
[28,] SKB1 0.33 ACTTGTCCTCAGCTTGGGCTTCTTC
[29,] GLTSCR2 0.37 AAGCCTATACGTTTCTGTGGAGTAA
[30,] CCNB1IP1 0.3 TCCTTGTGCCTGCTCCTGTACTTGT
[31,] MRPS2 0.33 TTGGACATCTCTAGTGTAGCTGCCA
= [32,] FL320859 0.34 TGCCTGCTCCTGTACTTGTCCTCAG
[33,] FLJ12270 0.3 ACTTGTCCTCAGCTTGGGCTTCTTC
Table 38. Bleomycin biomarkers.
Gene Correlation Probe Sequence
[1,1 PFN1 0.45 , GCCCCACTGGACAACACTGATTCCT
[2,] 1-IK1 0.33 TTGGACATCTCTAGTGTAGCTGCCA
[3,] MCL1 0.31 TGGACCCCACTGGCTGAGAATCTGG
93
CA 02631236 2008-05-26
WO 2007/072225
PCT/IB2006/004048
[4,] ZYX 0.32 TGGACCCCACTGGCTGAGAATCTGG
[5,] RAP12 0.34 ACTTGTCCTCAGCTTGGGCTTCTTC
[6,] GN22 0.32 CACCCAGCTGGTCCTGTGGATGGGA
[7,] EPAS1 0.31 ACTTGTCCTCAGCTTGGGCTTCTTC
[8,] PGAM1 0.42 TGCCTGCTCCTGTACTTGTCCTCAG
[9,] CKAP4 0.31 ACTTGTCCTCAGCTTGGGCTTCTTC
[10,] DUSP1 0.4 AAATGTTTCCTTGTGCCTGCTCCTG
[11,] MYL9 0.4 TTGGACATCTCTAGTGTAGCTGCCA
[12,] K-ALPHA-1 0.37 TTGGACATCTCTAGTGTAGCTGCCA
[13,] CSDA 0.3 TCCTTGTGCCTGCTCCTGTACTTGT
[14,] IFITM2 0.36 TTGGACATCTCTAGTGTAGCTGCCA
[15,] ITGA5 0.43 GCCCCACTGGACAACACTGATTCCT
[16,] DPYSL3 0.44 TGGACCCCACTGGCTGAGAATCTGG
[17,1 JUNE 0.32 TCCTGTACTTGTCCTCAGCTTGGGC
[18,] NFKBIA 0.32 TCCTCCATCACCTGAAACACTGGAC
[19,] LAM21 0.37 AAATGTTTCCTTGTGCCTGCTCCTG
[20,] FHLI 0.31 TGGACCCCACTGGCTGAGAATCTGG
[21,] INSIG1 0.31 TGGACCCCACTGGCTGAGAATCTGG
[22,] TIMP1 0.48 TGGACCCCACTGGCTGAGAATCTGG
[23,] GJAI 0.54 AAGCCTATACGTTTCTGTGGAGTAA
[24,1 PRG1 0.46 TCCTTGTGCCTGCTCCTGTACTTGT
[25,] EXT1 0.35 TCCTTGTGCCTGCTCCTGTACTTGT
[26,] DKFZP434J154 0.31 GCCCCACTGGACAACACTGATTCCT
[27,1 MVP 0.34 CACCCAGCTGGTCCTGTGGATGGGA
[28,] VASP 0.31 TCCTCCATCACCTGAAACACTGGAC
[29,] ARL7 0.39 TGGACCCCACTGGCTGAGAATCTGG
[30,] NNMT 0.34 TCCTGTACTTGTCCTCAGCTTGGGC
[31,] TAP1 0.3 TCCTGTACTTGTCCTCAGCTTGGGC
[32,] PLOD2 0.37 GCCCCACTGGACAACACTGATTCCT
[33,] AfF3 0.42 CACCCAGCTGGTCCTGTGGATGGGA
[34,] PALM2-AKAP2 0.33 TGGACCCCACTGGCTGAGAATCTGG
[35,] IL8 0.34 GCCCCACTGGACAACACTGATTCCT
[36,] LOXL2 0.32 GCCCCACTGGACAACACTGATTCCT
[37,1 IL4R 0.31 ACTTGTCCTCAGCTTGGGCTTCTTC
(38,1 DGKA 0.32 GCCCCACTGGACAACACTGATTCCT
[39,] SEC61G . 0.41 CACCCAGCTGGTCCTGTGGATGGGA
[40,1 RGS3 0.37 TGGACCCCACTGGCTGAGAATCTGG
[41,] F2R 0.34 CACCCAGCTGGTCCTGTGGATGGGA
[42,] TPM2 0.35 CACCCAGCTGGTCCTGTGGATGGGA
[43,] PSMB9 0.34 CACCCAGCTGGTCCTGTGGATGGGA
[44,] LOX 0.37 TCCTGTACTTGTCCTCAGCTTGGGC
[45,] STC1 0.35 TCCTCCATCACCTGAAACACTGGAC
[46,] PTGER4 0.31 CACCCAGCTGGTCCTGTGGATGGGA
[47,] SMAD3 0.38 TTGGACATCTCTAGTGTAGCTGCCA
[49,1 WNT5A 0.44 TGGACCCCACTGGCTGAGAATCTGG
[49,] BDNF 0.34 TCCTCCATCACCTGAAACACTGGAC
[50,] TNFRSFLA 0.46 TCCTCCATCACCTGAAACACTGGAC
[51,] FLNC 0.34 ACTTGTCCTCAGCTTGGGCTTCTTC
(52,1 DKFZP564K0822 0.34 TTGGACATCTCTAGTGTAGCTGCCA
[53,] FLOT1 0.38 TTGGACATCTCTAGTGTAGCTGCCA
[54,] PTRF 0.39 TGGACCCCACTGGCTGAGAATCTGG
[55,1 HLA-B 0.36 TTGGACATCTCTAGTGTAGCTGCCA
[56,] MGC4083 0.32 GCCCCACTGGACAACACTGATTCCT
[57,1 TNFRSF102 0.34 TGCCTGCTCCTGTACTTGTCCTCAG
- [58,] PLAGL1 0.31 TGCCTGCTCCTGTACTTGTCCTCAG
[59,] PNMA2 0.38 GCCCCACTGGACAACACTGATTCCT
[60,] TFPI 0.38 TCCTGTACTTGTCCTCAGCTTGGGC
94
CA 02631236 2008-05-26
WO 2007/072225
PCT/IB2006/004048
[61,] GZMB 0.51
TCCTCCATCACCTGAAACACTGGAC
[62,] PLAUR 0.35
AAGCCTATACGTTTCTGTGGAGTAA
[63,1 FSCN1 0.32 -
ACTTGTCCTCAGCTTGGGCTTCTTC
[64,] ERP70 0.32
ACTTGTCCTCAGCTTGGGCTTCTTC
[65,] AF1Q 0.3
TTGGACATCTCTAGTGTAGCTGCCA
[66,] HIC 0.33
TGCCTGCTCCTGTACTTGTCCTCAG
[67,1 COL6A1 0.32 .
AAGCCTATACGTTTCTGTGGAGTAA
[68,] IFITM3 0.3
GCCCCACTGGACAACACTGATTCCT
[69,] MAP1B 0.38
CACCCAGCTGGTCCTGTGGATGGGA
[70,] FLJ46603 0.37
TCCTCCATCACCTGAAACACTGGAC
71,] RAFTLIN 0.34
TGGACCCCACTGGCTGAGAATCTGG
[72,] RRAS 0.31
TCCTGTACTTGTCCTCAGCTTGGGC
[73,] FTL 0.3
CACCCAGCTGGTCCTGTGGATGGGA
[74,] KIAA0877 0.31
CACCCAGCTGGTCCTGTGGATGGGA
[75,] MT1E 0.31
TCCTTGTGCCTGCTCCTGTACTTGT
[76,] CDC10 0.51
AAATGTTTCCTTGTGCCTGCTCCTG
[77,1 DOCK2 0.32
AAGCCTATACGTTTCTGTGGAGTAA
[78,] RIS1 0.37
ACTTGTCCTCAGCTTGGGCTTCTTC
[79,] BCAT1 0.42
TTGGACATCTCTAGTGTAGCTGCCA
[80,] PRF1 0.34
TCCTCCATCACCTGAAACACTGGAC
[81,] DBN1 0.36
GCCCCACTGGACAACACTGATTCCT
[82,] MT1K 0.3
TGCCTGCTCCTGTACTTGTCCTCAG
[83,] TMSB10 0.42
GCCCCACTGGACAACACTGATTCCT
[84,] FLJ10350 0.4
AAATGTTTCCTTGTGCCTGCTCCTG
[85,] C1orf24 0.34
TGCCTGCTCCTGTACTTGTCCTCAG
[86,3 NME7 0.46
TCCTGTACTTGTCCTCAGCTTGGGC
[87,1 TMEM22 0.3
TGCCTGCTCCTGTACTTGTCCTCAG
[88,] TPK1 0.37
TCCTCCATCACCTGAAACACTGGAC =
[89,] ELK3 0.38
TGCCTGCTCCTGTACTTGTCCTCAG
[90,1 CYLD 0.4
TCCTTGTGCCTGCTCCTGTACTTGT
[91,1 ADAMTS1 0.31
AAGCCTATACGTTTCTGTGGAGTAA
[92,] EHD2 0.41
TCCTCCATCACCTGAAACACTGGAC
[93,3 ACTB 0.33
TCCTTGTGCCTGCTCCTGTACTTGT
Table 39. Methyl-GAG (methyl glyoxal bis amidinohydrazone dihydrochloride)
biomarkers.
Gene Correlation Probe Sequence
[1,] SSRP1 0.37
TGCCTGCTCCTGTACTTGTCCTCAG
[2,] CTSC 0.35
CACCCAGCTGGTCCTGTGGATGGGA
[3,] LBR 0.38
ACTTGTCCTCAGCTTGGGCTTCTTC
[4,] EFNB2 0.31
AAATGTTTCCTTGTGCCTGCTCCTG
[5,] SERPINA1 0.34 = TCCTTGTGCCTGCTCCTGTACTTGT
[6,] SSSCA1 0,32
TCCTGTACTTGTCCTCAGCTTGGGC
[7,] EZH2- = 0.36 TTGGACATCTCTAGTGTAGCTGCCA
[8,] MYB 0.33
GCCCCACTGGACAACACTGATTCCT
[9,] PRIM1 0.39
TCCTCCATCACCTGAAACACTGGAC
[10,] H2AFX 0.33
TCCTTGTGCCTGCTCCTGTACTTGT
[11,] HMGA1 0.35
TTGGACATCTCTAGTGTAGCTGCCA
[12,] HMMR 0.33
TCCTTGTGCCTGCTCCTGTACTTGT
[13,] TK2 0.42
CACCCAGCTGGTCCTGTGGATGGGA
[14,] WHSC1 0.35
AAATGTTTCCTTGTGCCTGCTCCTG
[15,] DIAPH1 0.34
GCCCCACTGGACAACACTGATTCCT
[16,] LAMB3 0.31
GCCCCACTGGACAACACTGATTCCT
[17,] DPAGT1 0.42
TGCCTGCTCCTGTACTTGTCCTCAG
[18,] UCK2 0.31
GCCCCACTGGACAACACTGATTCCT
[19,1 SERPINB1 0.31 TCCTTGTGCCTGCTCCTGTACTTGT
[20,] MDN1 0.35 TGCCTGCTCCTGTACTTGTCCTCAG
CA 02631236 2008-05-26
W02007/072225 PCT/IB2006/004048
[21,] GOS2 0.43 CACCCAGCTGGTCCTGTGGATGGGA
[22,] MGC21654 0.36 TGGACCCCACTGGCTGAGAATCTGG
[23,] GTSE1 0.35 ACTTGTCCTCAGCTTGGGCTTCTTC
[24,] TACC3 0.31 TCCTCCATCACCTGAAACACTGGAC
[25,] PLAC8 0.31 CACCCAGCTGGTCCTGTGGATGGGA
[26,] HNRPD 0.35 TTGGACATCTCTAGTGTAGCTGCCA
[27,]'PNAS-4 0.3 TTGGACATCTCTAGTGTAGCTGCCA
Table 40. HDAC inhibitors biomarkers.
Gene Correlation Probe Sequence
[1,] FAU 0.33 TTGGACATCTCTAGTGTAGCTGCCA
[2,] NOL5A 0.33 TGGACCCCACTGGCTGAGAATCTGG
[3,] ANP32A 0.32 CACCCAGCTGGTCCTGTGGATGGGA
[4,1 ARHGDIB 0.3 ACTTGTCCTCAGCTTGGGCTTCTTC
[5,] LBR 0.31 ACTTGTCCTCAGCTTGGGCTTCTTC
[6,] FABP5 0.33 TCCTCCATCACCTGAAACACTGGAC
[7,] ITM2A 0.32 TTGGACATCTCTAGTGTAGCTGCCA
[8,] SFRS5 0.34 TCCTCCATCACCTGAAACACTGGAC
[9,] IQGAP2 0.4 CACCCAGCTGGTCCTGTGGATGGGA
[10,] SLC7A6 0.35 AAGCCTATACGTTTCTGTGGAGTAA
[11,] SLA 0.31 TGCCTGCTCCTGTACTTGTCCTCAG
[12,] IL2RG 0.31 TCCTCCATCACCTGAAACACTGGAC
[13,] MFNG 0.39 TCCTGTACTTGTCCTCAGCTTGGGC
[14,] GPSM3 0.32 TTGGACATCTCTAGTGTAGCTGCCA
[15,] PIM2 0.3 TTGGACATCTCTAGTGTAGCTGCCA
[16,] EVER1 0.35 GCCCCACTGGACAACACTGATTCCT
[17,1 LRMP 0.35 TGCCTGCTCCTGTACTTGTCCTCAG
[18,1 ICAM2 0.44 TCCTGTACTTGTCCTCAGCTTGGGC
[19,] RIMS3 0.43 TGGACCCCACTGGCTGAGAATCTGG
[20,1 F14NL1 0.35 TTGGACATCTCTAGTGTAGCTGCCA
[21,1 MYB 0.37 TGCCTGCTCCTGTACTTGTCCTCAG
[22,] PTPN7 0.36 TCCTTGTGCCTGCTCCTGTACTTGT
[23,] LCK 0.48 CACCCAGCTGGTCCTGTGGATGGGA
[24,] CXorf9 0.3 ACTTGTCCTCAGCTTGGGCTTCTTC
[25,] RHOH 0.31 TCCTTGTGCCTGCTCCTGTACTTGT
[26,] ZNFN1A1 0.33 AAATGTTTCCTTGTGCCTGCTCCTG
[27,] CENTB1 0.45 CACCCAGCTGGTCCTGTGGATGGGA
[28,] LCP2 0.31 TGCCTGCTCCTGTACTTGTCCTCAG
[29,] DBT 0.32 TCCTGTACTTGTCCTCAGCTTGGGC
[30,1 CEP1 0.31 TTGGACATCTCTAGTGTAGCTGCCA
[31,1 IL6R 0.31 TGGACCCCACTGGCTGAGAATCTGG
[32,] VAV1 0.32 TCCTTGTGCCTGCTCCTGTACTTGT-
[33,] MAP4K1 0.3 AAGCCTATACGTTTCTGTGGAGTAA
[34,] CO28 0.36 TCCTTGTGCCTGCTCCTGTACTTGT
[35,] PTP4A3 0.3 TTGGACATCTCTAGTGTAGCTGCCA
[36,] CD3G 0.33 CACCCAGCTGGTCCTGTGGATGGGA
[37,] LTB 0.4 TCCTGTACTTGTCCTCAGCTTGGGC
[38,] USP34 0.44 GCCCCACTGGACAACACTGATTCCT
[39,] NVL 0.41 TCCTTGTGCCTGCTCCTGTACTTGT
[40,] CD8B1 0.33 ACTTGTCCTCAGCTTGGGCTTCTTC
[41,] SFRS6 0.31 GCCCCACTGGACAACACTGATTCCT
[42,] LCP1 0.34 TCCTGTACTTGTCCTCAGCTTGGGC
[43,] CXCR4 0.36 TGCCTGCTCCTGTACTTGTCCTCAG
[44,] PSCDBP 0.33 TGGACCCCACTGGCTGAGAATCTGG
[45,] SELPLG 0.33 TTGGACATCTCTAGTGTAGCTGCCA
[46,] CD3Z 0.3 TCCTTGTGCCTGCTCCTGTACTTGT
[47,] PRKCQ 0.33 TTGGACATCTCTAGTGTAGCTGCCA
96
CA 02631236 2008-05-26
WO 2007/072225
PCT/IB2006/004048
[48,] CDLA 0.34 GCCCCACTGGACAACACTGATTCCT
(49, GATA2 0.31 TTGGACATCTCTAGTGTAGCTGCCA
[50,] P2RX5 ' 0.32 TGCCTGCTCCTGTACTTGTCCTCAG
[51,] LAIR1 0.35 TGGACCCCACTGGCTGAGAATCTGG
[52,1 C1orf38 0.4 GCCCCACTGGACAACACTGATTCCT
[53,1 SH2D1A 0.44 TCCTTGTGCCTGCTCCTGTACTTGT
[54,] TRB@ 0.33 CACCCAGCTGGTCCTGTGGATGGGA
[55,] SEPT6 0.34 GCCCCACTGGACAACACTGATTCCT
[56,] HA-1 0.32 AAGCCTATACGTTTCTGTGGAGTAA
[57,] DOCK2 0.3 TCCTTGTGCCTGCTCCTGTACTTGT
[58,] WBSCR20C 0.31 TGCCTGCTCCTGTACTTGTCCTCAG
[59,] CD3D 0.3 ACTTGTCCTCAGCTTGGGCTTCTTC
[60,] RNASE6 0.31 GCCCCACTGGACAACACTGATTCCT
[61,] SFRS7 0.32 AAATGTTTCCTTGTGCCTGCTCCTG
[62,] WBSCR20A 0.3 AAGCCTATACGTTTCTGTGGAGTAA
[63,] NUP210 0.31 TTGGACATCTCTAGTGTAGCTGCCA.
[64,] C06 0.34 TCCTTGTGCCTGCTCCTGTACTTGT
[65,] HNRPA1 0.3 GCCCCACTGGACAACACTGATTCCT
[66,] AIF1 0.34 AAGCCTATACGTTTCTGTGGAGTAA
[67,] CYFIP2 0.38 TGGACCCCACTGGCTGAGAATCTGG
[68,] GLTSCR2 0.38 TCCTTGTGCCTGCTCCTGTACTTGT
[69,] Cllorf2 0.31 AAGCCTATACGTTTCTGTGGAGTAA
[70,] ARHGAP15 0.33 TGGACCCCACTGGCTGAGAATCTGG
[71,] BIN2 0.35 TTGGACATCTCTAGTGTAGCTGCCA
[72,] 5H3TC1 0.35 ACTTGTCCTCAGCTTGGGCTTCTTC
[73,] STAG3 0.32 AAATGTTTCCTTGTGCCTGCTCCTG
[74,] TM6SF1 0.34 ACTTGTCCTCAGCTTGGGCTTCTTC
[75,] C15orf25 0.33 T C CT CCATCACC T GAAACAC T GGAC
[76,] FL322457 0.36 AAATGTTTCCTTGTGCCTGCTCCTG
[77,] PACAP 0.34 TGCCTGCTCCTGTACTTGTCCTCAG
[78,] MGC2744 0.31 GC CCCACTGGACAACAC TGAT TCCT
Table 41. 5-Fluorouracil biomarkers.
Gene Correlation Probe Sequence
[1,] RPL18 0.38 AAATGTTTCCTTGTGCCTGCTCCTG
[2,] RPL10A 0.39 TGGACCCCACTGGCTGAGAATCTGG
[3,] ANAPC5 0.37 ACTTGTCCTCAGCTTGGGCTTCTTC
[4,1 EEF1B2 0.3 TCCTGTACTTGTCCTCAGCTTGGGC
[5,] RPL13A 0.5 TGCCTGCTCCTGTACTTGTCCTCAG
[6,] RPS15 0.4 ACTTGTCCTCAGCTTGGGCTTCTTC
[7,] NDUFAB1 0.38 GCCCCACTGGACAACACTGATTCCT
[8õ] APRT 0.32 AAATGTTTCCTTGTGCCTGCTCCTG
[9,] ZNF593 0.34 TCCTCCATCACCTGAAACACTGGAC
[10,] MRP63 0.32 AAATGTTTCCTTGTGCCTGCTCCTG
[11,] IL6R 0.41 TGGACCCCACTGGCTGAGAATCTGG
[12,] SART3 0.37 TCCTCCATCACCTGAAACACTGGAC
[13,] UCK2 0.32 GCCCCACTGGACAACACTGATTCCT
[14,] RPL17 0.31 AAGCCTATACGTTTCTGTGGAGTAA
[15,] RPS2 0.35 CACCCAGCTGGTCCTGTGGATGGGA
[16,] PCCB 0.38 TCCTTGTGCCTGCTCCTGTACTTGT
[17,] TOMM20 0_32 TGGACCCCACTGGCTGAGAATCTGG
118,1 SHMT2 0.32 TTGGACATCTCTAGTGTAGCTGCCA
[19,] RPLPO 0.31 TCCTTGTGCCTGCTCCTGTACTTGT
(20,1 GTF3A 0.32 CACCCAGCTGGTCCTGTGGATGGGA
[21,1 STOML2 0.33 TGGACCCCACTGGCTGAGAATCTGG
[22,] DKFZp564J157 0.4 AAATGTTTCCTTGTGCCTGCTCCTG
[23,1 MRPS2 0.32 TCCTGTACTTGTCCTCAGCTTGGGC
97
CA 02631236 2008-05-26
WO 2007/072225
PCT/IB2006/004048
[24 , ] ALG5 0 . 3 TTGGACATCTCTAGTGTAGCTGCCA
[25,] CALML4 0.33 CACCCAGCTGGTCCTGTGGATGGGA
Table 42. Radiation sensitivity biomarkers.
= =
Gene Correlation Probe Sequence
[1,] TRA1 0.36 TGGACCCCACTGGCTGAGAATCTGG
[2,] ACTN4 0.36 ACTTGTCCTCAGCTTGGGCTTCTTC
[3,] CALM1 0.32 TCCTCCATCACCTGAAACACTGGAC
[4,] CD63 0.32 TCCTGTACTTGTCCTCAGCTTGGGC
[5,1 FKBP1A 0.38 TGGACCCCACTGGCTGAGAATCTGG
[6,] CALU 0.47 ACTTGTCCTCAGCTTGGGCTTCTTC
[7,] IQGAP1 0.37 TTGGACATCTCTAGTGTAGCTGCCA
[8,] MGC8721 0.35 AAATGTTTCCTTGTGCCTGCTCCTG
[9,] STAT1 0.37 TGGACCCCACTGGCTGAGAATCTGG
[10,] TACC1 0.41 ACTTGTCCTCAGCTTGGGCTTCTTC
[11,] TM4SF8 0.33 AAGCCTATACGTTTCTGTGGAGTAA
[12,] 0D59 0.31 TCCTCCATCACCTGAAACACTGGAC
[13,] CKAP4 0.45 TCCTTGTGCCTGCTCCTGTACTTGT
[14,] DUSP1 0.38 TCCTGTACTTGTCCTCAGCTTGGGC
[15,] RCN1 0.31 TGCCTGCTCCTGTACTTGTCCTCAG
[16,] MGC8902 0.35 TGCCTGCTCCTGTACTTGTCCTCAG
[17,] RRBP1 0.31 ACTTGTCCTCAGCTTGGGCTTCTTC
[18,1 PRNP 0.42 TTGGACATCTCTAGTGTAGCTGCCA
[19,] IER3 . 0.34 GCCCCACTGGACAACACTGATTCCT
[20,] MARCKS 0.43 GCCCCACTGGACAACACTGATTCCT
[21,] FER1L3 0.47 TGCCTGCTCCTGTACTTGTCCTCAG
[22,1 SLC20A1 . 0.41 ACTTGTCCTCAGCTTGGGCTTCTTC
[23,] HEXB 0.46 AAATGTTTCCTTGTGCCTGCTCCTG
[24,] EXT1 0.47 CACCCAGCTGGTCCTGTGGATGGGA
[25,] TJP1 0.32 AAATGTTTCCTTGTGCCTGCTCCTG
[26,] CTSL 0.38 TCCTGTACTTGTCCTCAGCTTGGGC
[27,] SLC39A6 0.36 TCCTGTACTTGTCCTCAGCTTGGGC
[28,] RIOK3 0.38 TCCTCCATCACCTGAAACACTGGAC
[29,] CRK 0.37 TGCCTGCTCCTGTACTTGTCCTCAG
[30,] NNMT 0.37 TGCCTGCTCCTGTACTTGTCCTCAG
[31,] TRAM2 0.35 TTGGACATCTCTAGTGTAGCTGCCA
[32,] ADAM9 0.52 TCCTGTACTTGTCCTCAGCTTGGGC
[33,] PLSCR1 0.35 TGGACCCCACTGGCTGAGAATCTGG
[34,1 PRSS23 0.3 TGCCTGCTCCTGTACTTGTCCTCAG
[35,] FLOD2 0.36 TGCCTGCTCCTGTACTTGTCCTCAG
[36,1 NPC1 0.39 TGCCTGCTCCTGTACTTGTCCTCAG
[37,] TOB1 0.37 CACCCAGCTGGTCCTGTGGATGGGA
[38,] GFPT1 0.47 CACCCAGCTGGTCCTGTGGATGGGA
[39,] IL8 0.36 AAATGTTTCCTTGTGCCTGCTCCTG
[40,] PYGL 0.46 TCCTCCATCACCTGAAACACTGGAC
[41,] LOXL2 0.49 TTGGACATCTCTAGTGTAGCTGCCA
[42,] KIAA0355 . 0.36 TCCTTGTGCCTGCTCCTGTACTTGT
[43,] UGDH 0.49 TTGGACATCTCTAGTGTAGCTGCCA
[44,] PUPA 0.32 TGCCTGCTCCTGTACTTGTCCTCAG
[45,1 ULK2 0.37 AAGCCTATACGTTTCTGTGGAGTAA
[46,] CENTG2 0.35 GCCCCACTGGACAACACTGATTCCT
[47,] CAP350 0.31 GCCCCACTGGACAACACTGATTCCT
[48,] CXCL1 0.36 TCCTGTACTTGTCCTCAGCTTGGGC
[49,] BTN3A3 0.35 AAGCCTATACGTTTCTGTGGAGTAA
[50,] WNT5A 0.3 AAGCCTATACGTTTCTGTGGAGTAA
[51,1 FOXF2 0.44 AAATGTTTCCTTGTGCCTGCTCCTG
[52,] LPHN2 0.34 GCCCCACTGGACAACACTGATTCCT
98
CA 02631236 2008-05-26
WO 2007/072225
PCT/IB2006/004048
[5 3, ] =CD1-11 1 0.39 TGGACCCCACTGGCTGAGAATCTGG
[54,] P4HA1 0.33 TCCTCCATCACCTGAAACACTGGAC
[55,) GRP58 0.44 CACCCAGCTGGTCCTGTGGATGGGA
[56,] DSIPI 0.44 TGGACCCCACTGGCTGAGAATCTGG
[57,] MAP1LC3B 0.5 AAGCCTATACGTTTCTGTGGAGTAA
[58,] GALIG 0.36 AAATGTTTCCTTGTGCCTGCTCCTG
[59,) IGSF4 0.4 TCCTCCATCACCTGAAACACTGGAC
[60,] IRS2 0.35 TGGACCCCACTGGCTGAGAATCTGG
[61,] ATP2A2 0.35 CACCCAGCTGGTCCTGTGGATGGGA
[62,] OGT 0.3 TCCTGTACTTGTCCTCAGCTTGGGC
[63,] TNFRSF1OB 0.31 AAGCCTATACGTTTCTGTGGAGTAA
[64,] KIAA1128 0.35 CACCCAGCTGGTCCTGTGGATGGGA
[65,] TM4SF1 0.35 CACCCAGCTGGTCCTGTGGATGGGA
[66,] RIPK2 0.42 TGCCTGCTCCTGTACTTGTCCTCAG
[67,] NR1D2 0.47 TTGGACATCTCTAGTGTAGCTGCCA
[68,) SSA2 0.36 TTGGACATCTCTAGTGTAGCTGCCA
[69,] NQ01 0.4 AAGCCTATACGTTTCTGTGGAGTAA
[70,] ASPH 0.36 TGCCTGCTCCTGTACTTGTCCTCAG
[71,] MARI 0.33 ACTTGTCCTCAGCTTGGGCTTCTTC
[72,] MGLL 0.35 TGGACCCCACTGGCTGAGAATCTGG
[73,] SERPINB6 0.51 AAGCCTATACGTTTCTGTGGAGTAA
[74,] HSPA5 0.33 TCCTTGTGCCTGCTCCTGTACTTGT
[75,] ZFP36L1 0.39 TCCTTGTGCCTGCTCCTGTACTTGT
[76,] COL4A1 0.3 ACTTGTCCTCAGCTTGGGCTTCTTC
(77,) NIPA2 0.36 ACTTGTCCTCAGCTTGGGCTTCTTC
[78,) FKBP9 0.48 AAATGTTTCCTTGTGCCTGCTCCTG
[79,] IL6ST 0.4 GCCCCACTGGACAACACTGATTCCT
[80,] DKFZ2564G2022 0.39 TTGGACATCTCTAGTGTAGCTGCCA
[81,] PPAP2B 0.33 TGGACCCCACTGGCTGAGAATCTGG
[82,] MAP1B 0.3 CACCCAGCTGGTCCTGTGGATGGGA
[83,] MAPK1 0.3 TGGACCCCACTGGCTGAGAATCTGG
[84,) MY01B 0.38 ACTTGTCCTCAGCTTGGGCTTCTTC
(85,) CAST 0.31 TGCCTGCTCCTGTACTTGTCCTCAG
[86,] RRAS2 0.52 AAATGTTTCCTTGTGCCTGCTCCTG
[87,] QKI 0.31 ACTTGTCCTCAGCTTGGGCTTCTTC
[88,] LHFPL2 0.36 TCCTTGTGCCTGCTCCTGTACTTGT
[89,] SEPT10 0.38 GCCCCACTGGACAACACTGATTCCT
[90,] ARHE 0.5 AAGCCTATACGTTTCTGTGGAGTAA
[91,] KIAA1078 0.34 AAGCCTATACGTTTCTGTGGAGTAA
[92,] FTL 0.38 TCCTGTACTTGTCCTCAGCTTGGGC
[93,] KIAA0877 0.41 AAATGTTTCCTTGTGCCTGCTCCTG
[94,] PLCB1 0.3 AAGCCTATACGTTTCTGTGGAGTAA
[95,] KIAA0802 0.32 TGCCTGCTCCTGTACTTGTCCTCAG
[96,] RAB3GAP 0.43 TGCCTGCTCCTGTACTTGTCCTCAG
[97,] SERPINB1 0.46 TGCCTGCTCCTGTACTTGTCCTCAG
[98,] TIMM17A 0.38 AAATGTTTCCTTGTGCCTGCTCCTG
[99,] SOD2 0.35 TTGGACATCTCTAGTGTAGCTGCCA
[100,] HLA-A 0.33 TTGGACATCTCTAGTGTAGCTGCCA
[101,] NOM02 '0.43 CACCCAGCTGGTCCTGTGGATGGGA
(102,) L0055831 0.32 TCCTGTACTTGTCCTCAGCTTGGGC
[103,] PHLDA1 0.32 CACCCAGCTGGTCCTGTGGATGGGA
[104,] TMEM2 = 0.47 TGGACCCCACTGGCTGAGAATCTGG
[105,] MLPH 0.35 ACTTGTCCTCAGCTTGGGCTTCTTC
[106,] FAD104 0.34 ACTTGTCCTCAGCTTGGGCTTCTTC
[107,] LRRC5 0_42 CACCCAGCTGGTCCTGTGGATGGGA
[108,] R2B7L1 0.41 TTGGACATCTCTAGTGTAGCTGCCA
[109,] FLJ35036 0.36 TCCTGTACTTGTCCTCAGCTTGGGC
99
CA 02631236 2008-05-26
WO 2007/072225
PCT/IB2006/004048
[110,] DOCK10 0.41 TCCTCCATCACCTGAAACACTGGAC
[111,1 LRP12 0.36 AAGCCTATACGTTTCTGTGGAGTAA
[112,] TXNDC5 0.4 ACTTGTCCTCAGCTTGGGCTTCTTC
[113,1 CDC148 0.39 TGCCTGCTCCTGTACTTGTCCTCAG
[114,] HRMT1L1 0.38 CACCCAGCTGGTCCTGTGGATGGGA
[115,] DNAJC10 = 0.31 TTGGACATCTCTAGTGTAGCTGCCA
[116,] TNP01 0.33 GCCCCACTGGACAACACTGATTCCT
[117,] LONE 0.32 AAATGTTTCCTTGTGCCTGCTCCTG
[118,] AMIG02 0.38 AAGCCTATACGTTTCTGTGGAGTAA
[119,1 DNAPTP6 0.31 TGCCTGCTCCTGTACTTGTCCTCAG
[120,) ADAMTS1 0.37 TTGGACATCTCTAGTGTAGCTGCCA
Table 43. Mabthera (rituximab) biomarkers.
Gene Correlation Probe Sequence
[1,] PSMB2 0.89 TCCTCCATCACCTGAAACACTGGAC
[2,] BAT1 0.88 AAGCCTATACGTTTCTGTGGAGTAA.
= [3,] ASCC3L1 0.89 TCCTTGTGCCTGCTCCTGTACTTGT
[4,] SET 0.94 AAATGTTTCCTTGTGCCTGCTCCTG
[5,1 YWRAZ 0.83 TCCTTGTGCCTGCTCCTGTACTTGT
[6,] GLUL 0.8 TGGACCCCACTGGCTGAGAATCTGG
[7,] LDHA 0.8 TCCTTGTGCCTGCTCCTGTACTTGT
[8,] HMGBI 0.84 AAATGTTTCCTTGTGCCTGCTCCTG
[9,] SFRS2 0.87 AAATGTTTCCTTGTGCCTGCTCCTG
[10,] DPYSL2 0.82 TCCTGTACTTGTCCTCAGCTTGGGC
[11,] MGC8721 0.82. CACCCAGCTGGTCCTGTGGATGGGA
[12,] NOL5A 0.86 TGCCTGCTCCTGTACTTGTCCTCAG
[13,] SFRS10 0.88 AAATGTTTCCTTGTGCCTGCTCCTG
[14,] SF381 0.82 TCCTGTACTTGTCCTCAGCTTGGGC
[15,] K-ALPHA-1 0.86 TGCCTGCTCCTGTACTTGTCCTCAG
[16,1 TXNRD1 0.86 TGGACCCCACTGGCTGAGAATCTGG
[17,] ARHGDIB 0.83 CACCCAGCTGGTCCTGTGGATGGGA
[18,] ZFP36L2 0.92 TTGGACATCTCTAGTGTAGCTGCCA
[19,] DHX15 0.81 TGGACCCCACTGGCTGAGAATCTGG
[20,] SOX4 0.85 CACCCAGCTGGTCCTGTGGATGGGA
[21,] GRSF1 0.81 TGGACCCCACTGGCTGAGAATCTGG
[22,] MCM3 0.85 GCCCCACTGGACAACACTGATTCCT
[23,] IFITM1 0.82 TCCTCCATCACCTGAAACACTGGAC
[24,] RPA2 0.86 TCCTCCATCACCTGAAACACTGGAC
[25,] LEA 0.87 ACTTGTCCTCAGCTTGGGCTTCTTC
[26,3 CKS1B 0.85 AAGCCTATACGTTTCTGTGGAGTAA
[27,] NASP 0.82 TGGACCCCACTGGCTGAGAATCTGG
[26,] HNRPDL 0.81 TCCTCCATCACCTGAAACACTGGAC
[29,] CUGBP2 0.81 TGCCTGCTCCTGTACTTGTCCTCAG
[30,] PTBP1 0.87 TCCTTGTGCCTGCTCCTGTACTTGT
[31,] ARL7 0.83 TTGGACATCTCTAGTGTAGCTGCCA
[32,] CTCF 0.83 ACTTGTCCTCAGCTTGGGCTTCTTC
[33,] HMGCR 0.86 TCCTTGTGCCTGCTCCTGTACTTGT
[34,] ITM2A 0.88 AAATGTTTCCTTGTGCCTGCTCCTG
[35,] SFRS3 0.93 TCCTTGTGCCTGCTCCTGTACTTGT
[36,] SRPK2 0.82 TCCTTGTGCCTGCTCCTGTACTTGT
[37,] JARID2 0.92 CACCCAGCTGGTCCTGTGGATGGGA
[38,] M96 0.84 TCCTGTACTTGTCCTCAGCTTGGGC
[39,] MAD2L1 0.87 TCCTCCATCACCTGAAACACTGGAC
[40õ] SATEll 0.81 ACTTGTCCTCAGCTTGGGCTTCTTC
[41,] TMPO 0.9 ACTTGTCCTCAGCTTGGGCTTCTTC
[42,] SIVA 0.84 ACTTGTCCTCAGCTTGGGCTTCTTC
100
CA 02631236 2008-05-26
WO 2007/072225
PCT/IB2006/004048
(43,1 SEMA4D 0.9 TCCTCCATCACCTGAAACACTGGAC
[44,1 TFDP2 0.87 TCCTTGTGCCTGCTCCTGTACTTGT
[45,] SKP2 0.86 AAGCCTATACGTTTCTGTGGAGTAA
[46,1 SH3YL1 0.88 GCCCCACTGGACAACACTGATTCCT
[47,] RFC4 0.87 TCCTCCATCACCTGAAACACTGGAC
[48,] PCBP2 0.83 AAGCCTATACGTTTCTGTGGAGTAA
[49,1 IL2RG 0.84 GCCCCACTGGACAACACTGATTCCT
[50,] CDC45L 0.89 TCCTGTACTTGTCCTCAGCTTGGGC
[51,] GTSE1 0.83 TTGGACATCTCTAGTGTAGCTGCCA
[52,] KIF11 0.85 AAGCCTATACGTTTCTGTGGAGTAA
[53,] FEN1 0.88 TTGGACATCTCTAGTGTAGCTGCCA
[54,) MYB 0.9 TGGACCCCACTGGCTGAGAATCTGG
[55,1 LCK 0.87 TCCTCCATCACCTGAAACACTGGAC
[56,] CENPA 0.84 GCCCCACTGGACAACACTGATTCCT
[57,] CCNE2 0.84 GCCCCACTGGACAACACTGATTCCT
[58,] H2AFX 0.88 TTGGACATCTCTAGTGTAGCTGCCA
[59,] SNRPG 0.84 TCCTCCATCACCTGAAACACTGGAC
[60,] CD3G 0.94 TCCTTGTGCCTGCTCCTGTACTTGT
[61,] STK6 0.9 ACTTGTCCTCAGCTTGGGCTTCTTC
[62,1 PTP4A2 0.81 TGCCTGCTCCTGTACTTGTCCTCAG
[63,] FDFT1 0.91 AAATGTTTCCTTGTGCCTGCTCCTG
[64,] HSPA8 0.84 AAATGTTTCCTTGTGCCTGCTCCTG
[65,] HNRPR 0.94 TCCTTGTGCCTGCTCCTGTACTTGT
[66,] MCM7 0.92 AAATGTTTCCTTGTGCCTGCTCCTG
[67,] SFRS6 0_85 TGGACCCCACTGGCTGAGAATCTGG
[68,] PAK2 0.8 CACCCAGCTGGTCCTGTGGATGGGA
[69,] LCP1 0.85 TCCTGTACTTGTCCTCAGCTTGGGC
[70,] STAT3 0.81 ACTTGTCCTCAGCTTGGGCTTCTTC
[71,] OK/SW-c1.56 0.8 TCCTTGTGCCTGCTCCTGTACTTGT
[72r] WHSC1 0.81 TGGACCCCACTGGCTGAGAATCTGG
[73,] DIAPH1 0.88 AAGCCTATACGTTTCTGTGGAGTAA
[74,] KIF2C 0.88 TCCTGTACTTGTCCTCAGCTTGGGC
[75,] HDGFRP3 0.89 CACCCAGCTGGTCCTGTGGATGGGA
[76,] PNMA2 0.93 TTGGACATCTCTAGTGTAGCTGCCA
[77õ] GATA3 0.93 TCCTGTACTTGTCCTCAGCTTGGGC
[78,] BUB1 0.88 AAATGTTTCCTTGTGCCTGCTCCTG
[79,] TPX2 0.8 CACCCAGCTGGTCCTGTGGATGGGA
[80,) SH2D1A 0.86 TCCTTGTGCCTGCTCCTGTACTTGT
[81,] TNFAIP8 0.9 TCCTCCATCACCTGAAACACTGGAC
[82,] CSElL 0.83 AAATGTTTCCTTGTGCCTGCTCCTG
[83,] MCAM 0.8 TCCTGTACTTGTCCTCAGCTTGGGC
[84,] AF1Q 0.83 GCCCCACTGGACAACACTGAITCCT
[85,] CD47 0.86 CACCCAGCTGGTCCTGTGGATGGGA
[86,] SFRS1 0.85 AAGCCTATACGTTTCTGTGGAGTAA
[87,] FYB 0.92 TCCTGTACTTGTCCTCAGCTTGGGC
[88,] TRB@ 0.84 ACTTGTCCTCAGCTTGGGCTTCTTC
[89,] CXCR4 0.94 GCCCCACTGGACAACACTGATTCCT
[90,] H3F3B 0.84 TCCTCCATCACCTGAAACACTGGAC
[91,] MKI67 0.83 ACTTGTCCTCAGCTTGGGCTTCTTC
[92,1 MAC30 0.82 TCCTTGTGCCTGCTCCTGTACTTGT
[93,] ARID5B 0.88 AAGCCTATACGTTTCTGTGGAGTAA
[94,] L0C339287 0.81 AAGCCTATACGTTTCTGTGGAGTAA
[95,] CD3D 0.82 TCCTTGTGCCTGCTCCTGTACTTGT
[96,1 ZAP70 0.87 AAGCCTATACGTTTCTGTGGAGTAA
[97,] LAPTM4B 0.83 TCCTCCATCACCTGAAACACTGGAC
[98,] SFRS7 0.87 TCCTTGTGCCTGCTCCTGTACTTGT
[99,] HORPA1 0.9 AAGCCTATACGTTTCTGTGGAGTAA
101
CA 02631236 2008-05-26
WO 2007/072225
PCT/IB2006/004048
[100,1 HSPCA 0.88
AAGCCTATACGTTTCTGTGGAGTAA
[101,1 AIFI 0.22
TCCTTGTGCCTGCTCCTGTACTTGT
[102,] GTF3A 0.87
AAGCCTATACGTTTCTGTGGAGTAA
[103,] MCM5 0.91
TTGGACATCTCTAGTGTAGCTGCCA
[104,] GTL3 0.85
AAGCCTATACGTTTCTGTGGAGTAA
[105,1 ZNF22 0.89
TGCCTGCTCCTGTACTTGTCCTCAG
[106,1 FLJ22794 0.83
GCCCCACTGGACAACACTGATTCCT
[107,] LZTFL1 0.89
ACTTGTCCTCAGCTTGGGCTTCTTC
[108,] e(y)2 0.87
TCCTCCATCACCTGAAACACTGGAC
[109,] FLJ20152 0.92
TCCTCCATCACCTGAAACACTGGAC
[110,] C10orf3 0.86
ACTTGTCCTCAGCTTGGGCTTCTTC
[111,] NRN1 0.86
AAATGTTTCCTTGTGCCTGCTCCTG
[112,] FLJ10858 0.81
GCCCCACTGGACAACACTGATTCCT
[113,] BCL11B 0.89
GCCCCACTGGACAACACTGATTCCT
[114,] ASPM 0.91
AAGCCTATACGTTTCTGTGGAGTAA
[115,] LEF1 0.9
TTGGACATCTCTAGTGTAGCTGCCA
[116,] L0C146909 0.83
ACTTGTCCTCAGCTTGGGCTTCTTC
Table 44. 5-Aza-2'-deoxycytidine(decitabine) biomarkers.
Gene Correlation Probe Sequence
[1,] CD99 0.31 TTGGACATCTCTAGTGTAGCTGCCA
[2,] SNRPA 0.32 TCCTGTACTTGTCCTCAGCTTGGGC
[3,] CUGBP2 0.32 TCCTGTACTTGTCCTCAGCTTGGGC
[4,] STAT5A 0.32 GCCCCACTGGACAACACTGATTCCT
[5,] SLA 0.38 TTGGACATCTCTAGTGTAGCTGCCA
[6,] IL2RG 0.33 TGGACCCCACTGGCTGAGAATCTGG .
[7,] GTSE1 0.32 ACTTGTCCTCAGCTTGGGCTTCTTC
[8,] MYB 0.36 TGGACCCCACTGGCTGAGAATCTGG
[9,] PTPN7 0.33 TCCTGTACTTGTCCTCAGCTTGGGC
[10,] CXorf9 0.42 TCCTGTACTTGTCCTCAGCTTGGGC
[11,] RHOH 0.38 AAATGTTTCCTTGTGCCTGCTCCTG
[12,] ZNFN1A1 0.33 AAGCCTATACGTTTCTGTGGAGTAA
[13,1 CENTB1 0.35 CACCCAGCTGGTCCTGTGGATGGGA
[14,] LCP2 0.3 AAATGTTTCCTTGTGCCTGCTCCTG
[15,] HIST1H4C 0.33 TGGACCCCACTGGCTGAGAATCTGG
[16,] CCR7 0.37 TGCCTGCTCCTGTACTTGTCCTCAG
[17,] APOBEC3B 0.31 TCCTTGTGCCTGCTCCTGTACTTGT
[18,] MCM7 0.31 TGGACCCCACTGGCTGAGAATCTGG
[19.1 LCP1 0.31 AAGCCTATACGTTTCTGTGGAGTAA
[20,] SELPLG 0.4 TGGACCCCACTGGCTGAGAATCTGG
[21,] CD3Z 0.35 TCCTGTACTTGTCCTCAGCTTGGGC
[22,] PRKCQ 0.39 TGCCTGCTCCTGTACTTGTCCTCAG.
[23,] GZMB 0.32
GCCCCACTGGACAACACTGATTCCT .
[24,] SCN3A 0.4 AAGCCTATACGTTTCTGTGGAGTAA
[25,] LAIR1 0.35 TGCCTGCTCCTGTACTTGTCCTCAG
[26,] SH2D1A 0.35 GCCCCACTGGACAACACTGATTCCT
[27,] SEPT6 0.35 ACTTGTCCTCAGCTTGGGCTTCTTC
[28,] CG018 0.32 ACTTGTCCTCAGCTTGGGCTTCTTC
[29,] CD3D 0.31 TGGACCCCACTGGCTGAGAATCTGG
[30,] C18orf10 0.33 TCCTTGTGCCTGCTCCTGTACTTGT
[31,] PRF1 0.31 TCCTCCATCACCTGAAACACTGGAC
[32,] AIF1 0.31 TTGGACATCTCTAGTGTAGCTGCCA
[33,] MCM5 0.31 ACTTGTCCTCAGCTTGGGCTTCTTC
[34,] LPXN 0.35 TCCTCCATCACCTGAAACACTGGAC
[35,] C22orf18 0.33 AAATGTTTCCTTGTGCCTGCTCCTG
[36,] ARHGAP15 0.31 AAATGTTTCCTTGTGCCTGCTCCTG
[37,] LEF1 0.43 GCCCCACTGGACAACACTGATTCCT
102
CA 02631236 2008-05-26
WO 2007/072225
PCT/IB2006/004048
What is claimed is:
103
DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.
CECI EST LE TOME 1 DE 2
CONTENANT LES PAGES 1 A 103
NOTE : Pour les tomes additionels, veuillez contacter le Bureau canadien des
brevets
JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME
THIS IS VOLUME 1 OF 2
CONTAINING PAGES 1 TO 103
NOTE: For additional volumes, please contact the Canadian Patent Office
NOM DU FICHIER / FILE NAME:
NOTE POUR LE TOME / VOLUME NOTE:
